1. Emerging Role of Maintenance Treatment in Ovarian Cancer
GEMSTONE Educational Module
Last Update: June 27, 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 Define maintenance therapy for ovarian cancer
Describe rationale behind maintenance therapy
Review clinical trials investigating maintenance therapy for ovarian cancer
Explore current evidence for effect of maintenance therapy on quality of life

3. Module Outline Defining Maintenance Therapy
Rationale Behind Maintenance Therapy
Clinical Studies Investigating Maintenance Therapy for Ovarian Cancer
Quality of Life in Maintenance Trials
Maintenance Adoption in the Real World
Summary and Unresolved Questions

4. Defining Maintenance Therapy

5. Maintenance Therapy Is Extended Therapy With Goal of Prolonging PFS
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 after 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 after initial therapy; 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 April 9, ASCO. Understanding Maintenance Therapy. Cancer.net. Approved October Accessed April 9, Schmid-Bindert G. Transl Lung Cancer Res. 2012;1(2):

6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Recommend Maintenance Therapy as an Option for Patients in Response to Platinum-Based Chemotherapya
Platinum-refractory
Progression, stable, or persistent disease on primary chemotherapy
Recurrence therapy
Preferred options include: Single-agent chemo, chemo and targeted therapy combination, or targeted therapy monotherapya
Clinical trials
BSC
AND/OR
AND/OR
Platinum-resistant
Complete remission and relapse <6 mo after completing chemotherapy
Clinical Trial
Platinum-sensitive
Complete remission and relapseb ≥6 mo after completing prior chemotherapy OR
Platinum-based combination therapy preferred for first recurrence
Consider secondary cytoreductive surgery
If partial or complete response: Maintenance therapya,d
Clinical trials
Recurrence therapya,c
BSC
AND/OR OR
AND/OR OR
Observe
a For detailed recommendations (including recommended recurrence therapy regimens and maintenance therapy), see the complete version of the NCCN Guidelines for Ovarian Cancer. b Guideline recommendations for radiographic and/or clinical relapse are shown. c Preferred options include: Combination chemotherapy, chemotherapy and targeted therapy combination, and single- agent targeted therapy. d Maintenance therapy is an option for patients who have responded to platinum-based recurrence therapy and who have not progressed.
BSC, best supportive care; chemo, chemotherapy; NCCN, National Comprehensive Cancer Network.
NCCN Guidelines® Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V ). Available online at NCCN.org. Accessed April 9, 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 © 2018 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data become available. 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. 6

7. Rationale Behind Maintenance Therapy

8. 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):

9. Goal of Therapy for Recurrence Is Extending PFS While Maintaining QoL
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; QoL, quality of life. 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 April 9, 2018.

10. SGO and FDA Recommend PFS as an Endpoint for Phase 3 Clinical Studies in Ovarian Cancer
Efficacy Endpoint Considerations1
Frontline
Platinum-Sensitive
Platinum-Resistant
Clear Cell Mucinous
LG-Serous OS
Approve
PFS (statistically significant) + other (QoL/PRO)
Considera
PFS (statistically significant) with clinically meaningful magnitude of effect
ORR (with supportive duration of response) No
a In addition to statistically significant differences, other means of benefit would need to be demonstrated such as significant difference in time off therapy or at least an OS trend.2
FDA, US Food and Drug Administration; LG, low-grade; OS, overall survival; ORR, objective response rate; PFS, progression-free survival; PRO, patient-reported outcomes; QoL, quality of life; SGO, Society of Gynecologic Oncology.
1. Herzog TJ, et al. Gynecol Oncol. 2017;147(1): Herzog TJ, et al. Gynecol Oncol. 2014;132(1):8-17.

11. Prior to Bevacizumab and PARPi, Many Therapies Proved Ineffective as Maintenance
Clinical Benefit
Strategy No
Yes
Prolonged initial therapy1,2 ✓
Consolidation therapy with topotecan3
High-dose/shorter interval chemotherapy4
Intraperitoneal5
Interferon-6
Oregovomab7
Erlotinib8
Tanomastat9
Abagovomab10
Paclitaxel (6 months)11
Paclitaxel (12 months)12
1. Lambert HE, et al. Ann Oncol. 1997;8(4): Bertelsen K, et al. Gynecol Oncol. 1993;49(1): De Placido S, et al. J Clin Oncol. 2004;22(13): Chan JK, et al. N Engl J Med. 2016;374(8): Barakat RR, et al. J Clin Oncol. 2002;20(3): Hall GD, et al. Br J Cancer. 2004;91(4): Berek J, et al. J Clin Oncol. 2009;27(3): Vergote IB, et al. J Clin Oncol. 2014;32(4): Hirte H, et al. Gynecol Oncol. 2006;102(2): Sabbatini P, et al. J Clin Oncol. 2013;31(12): Conte PF, et al. J Clin Oncol. 2007;25(18 suppl):abstr Markman M, et al. J Clin Oncol. 2003;21(13):

12. Range of mPFS Reported in Studies, mo
In Clinical Trials, PARPi Maintenance Therapy Was More Effective Than Observation for Many Patients
Patient Population
Treatment Arm
Range of mPFS Reported in Studies, mo
PSOC1-3
Chemo alone
8.4–10.4
Chemo + anti-angiogenic therapy
11.1–13.8
gBRCAmut or BRCAmut ovarian cancer in response to platinum4-7,a
Placebo
4.3–5.5
PARPi
11.2–21.0
Non-gBRCAmut or BRCAwt ovarian cancer in response to platinum5,7
3.9–5.5
7.4–9.3
This time does not reflect 4–6 mo of induction chemotherapy that precedes maintenance treatment
Trials are not designed or intended for direct comparison.
a Data from clinical trial patient subgroups defined by presence of a germline mutation, a germline or somatic mutation, or specifically a deleterious germline or somatic mutation in BRCA1/2.
BRCA, breast cancer susceptibility gene; chemo, chemotherapy; g, germline; mPFS, median progression-free survival; mut, mutation; PARPi, poly ADP ribose polymerase inhibitor; PSOC, platinum-sensitive ovarian cancer; wt, wild-type.
1. Coleman RL, et al. Lancet Oncol. 2017;18(6): Ledermann JA, et al. Presented at ASCO Annual Meeting, Abstract Aghajanian C, et al. J Clin Oncol. 2012;30(17): Coleman RL, et al. Lancet ;390(10106): Ledermann J, et al. Lancet Oncol. 2014;15(8): Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9): Mirza MR, et al. N Engl J Med. 2016;375(22):

13.    Effective Manageable Adverse Effects Convenient
Requirements for Long-Term Treatments Apply When Considering Maintenance Therapy 
Effective 
Manageable Adverse Effects 
Convenient
1. Hope JM, et al. Int J Womens Health. 2009;1: Korkmaz T, et al. Crit Rev Oncol Hematol. 2016;98:180-8.

14. Clinical Studies Investigating Maintenance Therapy for Ovarian Cancer

15. Landmark FDA Approvals in Ovarian Cancer Therapy1
Bevacizumaba (platinum- sensitive)
Treatment
Maintenance
Rucaparib (platinum- sensitive)
Altretamine
Topotecan
Liposomal Doxorubicin (Full)
Bevacizumab (platinum- resistant)
Bevacizumaba (after initial resection)
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)
a In combination with carboplatin and paclitaxel, followed by bevacizumab alone.
FDA, US Food and Drug Administration; L, line; mut, mutation.
1. FDA Approved Drug Products. Accessed March 29, April 9, and June 13, Kelland L. Nat Rev Cancer. 2007;7(8):

16. Summary of FDA-Approved Maintenance Treatment Indications
Agent
Current Label
Registrational Trial Name(s)
Label Dosing and Scheduling
Bevacizumab1,2
As combination with CP or CG, followed by monotherapy for ROC in response to platinum
OCEANS
(phase 3)
GOG-0213
IV infusion 15 mg/kg q3w
As combination with CP, followed by monotherapy for stage III/IV OC following initial surgical resection
GOG (phase 3)
Olaparib3
2L+ PSOC maintenance
Study 19
(phase 2)
SOLO-2
300 mg (two 150-mg tablets) PO bid
Niraparib4
NOVA
300 mg (three 100-mg capsules) PO daily
Rucaparib5
ARIEL 3
600 mg (two 300-mg tablets) PO bid
bid, twice daily; CG, carboplatin/gemcitabine; CP, carboplatin/paclitaxel; FDA, US Food and Drug Administration; IV, intravenous; L, line; OC, ovarian cancer; PO, orally; PSOC, platinum-sensitive ovarian cancer; q3w, every 3 weeks; ROC, recurrent ovarian cancer.
1. Bevacizumab package insert. Genentech, Inc; June Roche's Bevacizumab Plus Chemotherapy Receives FDA Approval for Platinum-sensitive Recurrent Ovarian Cancer [press release]. Basel, Switzerland: Roche; December 7, Accessed April 9, Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Niraparib package insert. TESARO, Inc; August Rucaparib package insert. Clovis Oncology, Inc; April 2018.

17. Additional Taxane Maintenance Did Not Alter OS
Progression was slightly delayed with additional chemotherapy1
Neither GOG-0178 or GOG-0212 demonstrated an effect of taxane maintenance on overall survival1,2
Additional taxane therapy increases grades 3 to 4 adverse events, most notably neurotoxicity2
GOG-0212 (NCT )
Treatment Group
Events n
mOS, mo
Paclitaxel
206
384
51.3
Paclitaxel poliglumex (CT-2103)
194
387
60.0
Surveillance
200
386
54.8
mOS, median overall survival; OS, overall survival.
1. Markman M, et al. J Clin Oncol. 2003;21(13): Copeland LJ, et al. Presented at SGO Annual Meeting, 2017.

18. Study Designs of Key Anti-Angiogenic Maintenance Therapy Trials in Recurrent 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):

19. Chemo + Conc./ Maint. CED (n=164)
Data Summary for Key Anti-Angiogenic Maintenance Therapy Trials in Recurrent PSOC
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.
AE, adverse event; 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; PSOC, platinum-sensitive ovarian cancer.
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):

20. Study Designs of Key Anti-Angiogenic Maintenance Therapy Trials in Front-Line Ovarian Cancer Setting
AGO-OVAR (NCT )
GOG
(NCT ) N
940
1873
Design
Phase 3, randomized
Patient population
Stage II–IV epithelial ovarian, fallopian tube, or primary peritoneal cancer; CR, PR, or SD on 1L chemo
Previously untreated, incompletely resected stage III or any stage IV epithelial ovarian, primary peritoneal, or fallopian tube cancer
Study arms
Placebo comparator: PBO
Experimental: PAZ
Active comparator: CP + PBO  PBO
Experimental: CP + BEV  PBO
Experimental: CP + BEV  BEV
Dosage
PAZ 800 mg daily for 24 mo
Cycles 1–6: C AUC 6, P 175 mg/m2
Cycles 2–6: PBO q3w or BEV 15 mg/kg q3w
Cycles 7–22: PBO q3w or BEV 15 mg/kg q3w
1⁰ Endpoint
PFS by RECIST
PFS by RECIST or GCIG criteria
2⁰ Endpoint
OS, PFS by GCIG criteria, 3-y PFS rate, QoL, safety
OS, safety, QoL
Stratification factors
1L treatment outcome, region
GOG performance status score, cancer stage, debulking status
AUC, area under the curve; BEV, bevacizumab; C, carboplatin; Chemo, chemotherapy; CR, complete response; GCIG, Gynecological Cancer InterGroup; GOG, Gynecologic Oncology Group; L, line; OS, overall survival; P, paclitaxel; PAZ, pazopanib; PBO, placebo; PFS, progression-free survival; PR, partial response; q3w, every 3 weeks; QoL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.
1. ClinicalTrials.gov. NCT Accessed June 27, du Bois A, et al. J Clin Oncol. 2014;32(30): Vergote I, et al. Presented at ASCO Annual Meeting, Abstract ClincialTrials.gov. NCT Accessed June 27, Burger RA, et al. New Engl J Med. 2011;365(26): Burger RA, et al. Presented at ASCO Annual Meeting, Abstract 5517.

21. Data Summary for Key Anti-Angiogenic Maintenance Therapy Trials in Front-Line Ovarian Cancer Setting
AGO-OVAR (NCT )
GOG
(NCT )
PBO (n=468)
PAZ (n=472)
CP + PBO  PBO (n=625)
CP + BEV  PBO (n=625)a
CP + BEV  BEV (n=623)a
mPFS, mo (95% CI)
12.3
(11.8–17.7)
17.9
(15.9–21.8) 
10.3 (NR)
11.2
(NR)
14.1
HR (95% CI) P value
0.77 (0.64–0.91)
0.0021 --
0.908 (0.795–1.040)b 0.16
0.717 (0.625–0.824)b <0.001
mOS, mo (95% CI)
64.0 (56.0–75.7)
59.1 (53.5–71.6)
41.1 (NR)
40.8
43.4
0.960 (0.805–1.145)
1.06 (0.94–1.20)b 0.34
0.96 (0.85–1.09)b 0.53
Most Common Serious AEs (%)
Hypertension (Gr 3/4): 5.6
Neutropenia (Gr 3/4): 1.5
Diarrhea (Gr 3/4): 1.1 Abdominal pain (Gr 3/4): 1.1
Hypertension (Gr 3/4): 30.8
Neutropenia (Gr 3/4): 9.9
Liver-related toxicity (Gr 3/4): 9.4
Neutropenia (Gr ≥4): 57.7
Pain (Gr ≥2): 41.6 Hypertension (Gr ≥2):
7.2
Neutropenia (Gr ≥4): 63.3
Pain (Gr ≥2): 41.5 Hypertension (Gr ≥2): 16.5
Pain (Gr ≥2): 47.0 Hypertension (Gr ≥2): 22.9
The direct cross-study comparison of results from independently conducted clinical trials is not intended on this slide.
a Safety results reported for 607 and 608 patients in the CP + BEV  PBO and CP + BEV BEV arms, respectively. b HR and P values calculated vs CP  PBO arm.
AE, adverse event; BEV, bevacizumab; CI, confidence interval; CP, carboplatin/paclitaxel; Gr, grade; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; NR, not reported; PAZ, pazopanib; PBO, placebo.
1. ClinicalTrials.gov. NCT Accessed June 27, du Bois A, et al. J Clin Oncol. 2014;32(30): Vergote I, et al. Presented at ASCO Annual Meeting, Abstract ClincialTrials.gov. NCT Accessed June 27, Burger RA, et al. New Engl J Med. 2011;365(26): Burger RA, et al. Presented at ASCO Annual Meeting, Abstract 5517.

22. Anti-Angiogenic Maintenance Summary
Anti-angiogenic agents improve PFS in recurrence treatment, as well as in front-line treatment, of ovarian cancer1-5
Significant durable effect on OS has not been shown consistently for anti-angiogenic agents2,6-9
Anti-angiogenic maintenance therapy was associated with increased vascular adverse reactions, bleeding events, and other AEs compared with placebo, and varied by agent used2-4,6
AE, adverse event; OS, overall survival; PFS, progression-free survival.
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): du Bois A, et al. J Clin Oncol. 2014;32(30): Burger RA, et al. New Engl J Med. 2011;365(26): Aghajanian C, et al. Gynecol Oncol. 2015;139(1): Ledermann JA, et al. Presented at ASCO Annual Meeting, Abstract Burger RA, et al. Presented at ASCO Annual Meeting, Abstract Vergote I, et al. Presented at ASCO Annual Meeting, Abstract 5518.

23. 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, and 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):

24. PARPi Maintenance Summary
PARPi 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
PARPi treatment is associated with hematologic 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 module on PARP inhibition for more efficacy and safety data
AE, adverse event; OS, overall survival; PARPi, poly ADP ribose polymerase inhibitor; 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):

25. Quality of Life in Maintenance Trials

26. GOG-0212: Extended Taxane Does Not Significantly Decrease Overall QoL
Patient-Reported FACT-O TOI Score
Better
P vs S
PP vs S
PP vs P S P PP 90 80 70 60 50
FACT-O TOI
S Surveillance P Paclitaxel PP CT-2103
77.4
80.0
80.8
79.5
79.2
77.3
76.9
77.6
77.5
76.8
76.0
78.2
78.8
79.3
78.3
Baseline
Cycle 3
Cycle 5
Cycle 7
Cycle 12
12 months
Least Squares Means Differences (99% CI)
-2.9 (-4.7 to -1.0)a
-3.4 (-5.4 to -1.3)a
-2.3 (-4.7 to 0.0)
-2.5 (-5.0 to 0.0)
-0.5 (-3.5 to 2.6)
-1.7 (-3.5 to 0.1)
-2.1 (-4.1 to -0.1)
0.1 (-2.2 to 2.3)
-1.1 (-3.7 to 1.5)
1.4 (-1.6 to 4.4)
1.2 (-0.6 to 2.9)
1.3 (-0.7 to 3.4)
2.4 (0.2 to 4.6)
1.4 (-0.9 to 3.7)
1.9 (-1.1 to 4.8)
a Statistically significant result.
CI, confidence interval; FACT-O TOI, Functional Assessment of Cancer Therapy–Trial Outcome Index; QoL, quality of life.
Copeland LJ, et al. Presented at SGO Annual Meeting, 2017.

27. GOG-0213: Addition of Bevacizumab to Chemotherapy Altered Physical Functioning, But Not QoL
Patient-Reported FACT-O TOI Score
By Treatment Groups
Patient-Reported Physical Functioning Score
By Treatment Groups
No Bevacizumab
Bevacizumab
No Bevacizumab
Bevacizumab
Treatment with bevacizumab had no significant effect on HRQoL, as measured by the FACT-O TOI.
Exploratory analysis revealed that physical functioning was lower in the bevacizumab arm during, but not after, treatment.
FACT-O, Functional Assessment of Cancer Therapy-Ovarian Cancer; HRQoL, health-related quality of life; QoL, quality of life; TOI, Trial Outcome Index.
Basen-Engquist K, et al. Presented at ASCO Annual Meeting, Abstract 9633.

28. Studies That Have Included QoL Measurements Show No Clinical Effect of Maintenance Therapy
Study
Effect on Overall QoL
Extended taxanes
GOG-01781
Not included
GOG-02122
No clinical effect
Anti-angiogenics
OCEANS3
GOG-02134
ICON65
AGO-OVAR 16
Not yet presented
PARP inhibitors
NOVA6
SOLO-27,8
Study 199
ARIEL3
No clinical effect: Please refer to the module on PARP inhibition for more QoL data
PARP, poly ADP ribose polymerase; QoL, quality of life.
1. Hope JM, et al. Int J Womens Health. 2009;1: Copeland LJ, et al. Presented at SGO Annual Meeting, Della Pepa C, et al. Onco Targets Ther. 2014;7: Basen-Engquist K, et al. Presented at ASCO Annual Meeting, Abstract Ledermann JA, et al. Lancet. 2016;387(10023): Oza A, et al. Presented at ESMO Annual Meeting, Abstract 930O. 7. Pujade-Lauraine E, et al. Presented at SGO Annual Meeting, Friedlander M, et al. Presented at ASCO Annual Meeting, Abstract Ledermann J, et al. N Engl J Med ;366(15):

29. Maintenance Adoption in the Real World

30. New England Journal of Medicine
PARPi Maintenance Therapy Was Evaluated in 1412 Women Across Three Phase 3 Studies1-3
Lancet
Rucaparib Maintenance Treatment for Recurrent Ovarian Carcinoma After Response to Platinum Therapy (ARIEL3): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial
RL Coleman, AM Oza, D Lorusso, C Aghajanian, A Oaknin, A Dean, N Colombo, JI Weberpals, A Clamp, G Scambia, A Leary, RW Holloway, M Amenedo Gancedo, PC Fong, JC Goh, DM O’Malley, DK Armstrong, J Garcia-Donas, EM Swisher, A Floquet, GE Konecny, IA McNeish, CL Scott, T Cameron, L Maloney, J Isaacson, S Goble, C Grace, TC Harding, M Raponi, J Sun, KK Lin, H Giordano, JA Ledermann, on behalf of the ARIEL3 investigators
New England Journal of Medicine
Niraparib Maintenance Therapy in Platinum- Sensitive, Recurrent Ovarian Cancer
MR Mirza, BJ Monk, J Herrstedt, AM Oza, S Mahner, A Redondo, M Fabbro, JA Ledermann, D Lorusso, I Vergote, NE Ben-Baruch, C Marth, R Mądry, RD Christensen, JS Berek, A Dørum, AV Tinker, A du Bois, A González-Martín, P Follana, B Benigno, P Rosenberg, L Gilbert, BJ Rimel, J Buscema, JP Balser, S Agarwal, and UA Matulonis, for the ENGOT-OV16/NOVA Investigators
Lancet Oncology
Olaparib Tablets as Maintenance Therapy in Patients With Platinum-Sensitive, Relapsed Ovarian Cancer and a BRCA1/2 Mutation (SOLO2/ENGOT-Ov21): A Double-Blind, Randomised, Placebo-Controlled, Phase 3 Trial
E Pujade-Lauraine, JA Ledermann, F Selle, V Gebski, RT Penson, AM Oza, J Korach, T Huzarski, A Poveda, S Pignata, M Friedlander, N Colombo, P Harter, K Fujiwara, I Ray-Coquard, S Banerjee, J Liu, ES Lowe, R Bloomfield, P Pautier, the SOLO2/ENGOT-Ov21 investigators
PARPi, poly ADP ribose polymerase inhibitor. 1. Mirza MR, et al. N Engl J Med. 2016;375(22): Coleman RJ, et al. Lancet. 2017;390(10106): Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):

31. 2L+ Maintenance Eligiblea Share Regardless of BRCA Mutational Status
Despite Its Demonstrated Efficacy, Less Than 40% of Eligible Women Currently Receive Maintenance Therapy
2L+ Maintenance Eligiblea Share Regardless of BRCA Mutational Status
Platinum agent
Taxane
Bevacizumab
PARP inhibitor
Watch and wait
Percent of Patients
(n=117)
(n=131)
(n=180)
Data through:
January 31, 2018
February 28, 2018
March 31, 2018
a Maintenance eligibility criteria: Patients who received ≥4 cycles of platinum for 2L+ treatment between March and March 2018.
2L, second line; BRCA, breast cancer susceptibility gene; PARP, poly ADP ribose polymerase.
Data from Flatiron Health, January through March

32. Summary and Unresolved Questions

33. Module Summary
Goal of maintenance therapy is to prolong PFS through continued treatment1
Maintenance therapy should be an effective, tolerable, and convenient therapy2
Current agents that may be considered for maintenance therapy are anti-angiogenic agents and PARP inhibitors3-6
Consideration of risk-benefit and convenience for patients can help guide appropriate treatment decisions7
PARP, poly ADP ribose polymerase; PFS, progression-free survival.
1. ASCO. Understanding Maintenance Therapy. Cancer.net. treated/understanding-maintenance-therapy. Approved October Accessed April 9, Korkmaz T, et al. Crit Rev Oncol Hematol. 2016;98: Bevacizumab package insert. Genentech, Inc; June Olaparib package insert. AstraZeneca Pharmaceuticals LP; January Niraparib package insert. TESARO, Inc; August Rucaparib package insert. Clovis Oncology, Inc; April Qian X, et al. PLoS One. 2015;10(9):e

34. Unresolved Questions
What is the appropriate duration of therapy in patients free of disease?
Are there differences in benefit of maintenance therapy for patients in PR vs CR at the end of chemotherapy?
How do we understand cost-effectiveness of maintenance therapy?
How do you choose between bevacizumab and PARP inhibitors when deciding on maintenance therapy for patients who qualify for treatment with both?
Will trials evaluating maintenance therapy with PARP inhibitors demonstrate OS benefit?
How do you choose among different PARP inhibitors for maintenance therapy?
CR, complete response; OS, overall survival; PARP, poly ADP ribose polymerase; PR, partial response.

35. 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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