1. The latest clinical evidence on PARP inhibitor maintenance therapy
Dr Rebecca Kristeleit Clinical Senior Lecturer & Consultant Medical Oncologist UCL Cancer Institute / UCL Hospitals, London, UK
ESMO 2018
Munich, Germany

2. Advanced ovarian cancer: a ‘chronic’ disease with multiple relapses
Platinum-sensitive relapses
Platinum-resistant relapses
First line *
Surgery
Occlusion
Tumour volume (CA-125 MU/ml)
PFI: 12 months
>8 months
Goal of maintenance therapy: to extend the progression-free interval1
Disease-free survival (months)
PFI, platinum-free interval or duration of disease control without chemotherapy
Figure adapted from: Giornelli GH, et al. SpringerPlus 2016;5:1197.

3. Could maintenance therapy be an alternative option?
Switch maintenance
treating a patient with a targeted drug immediately after a patient attains maximal response to chemotherapy
Chemotherapy
Maintenance targeted therapy
Continuation maintenance
the patient continues to receive a targeted drug, after initial therapy with that drug in combination with chemotherapy
Targeted therapy
Chemotherapy
Maintenance targeted therapy

4. Standard practice maintenance strategies in ovarian cancer
Anti-angiogenesis
PARP inhibitors

5. Published PFS results in maintenance therapy studies
Anti-angiogenesis
BRCA status not determined
PARP inhibition
gBRCA patients
non-gBRCA patients
Chemotherapy 6 months
Phase 3
SOLO23
5.5
N=80
19.1
N=196
NOVA1 21
N=138
N=65
11.2
N=74
4.3
N=62
ARIEL34
16.6
N=130
5.4
N=66
3.9
9.3
N=116
N=234
Phase 2
Study 192 5 10 15 20
7.4
N=57
N=61
Δ15.5
Δ6.9
Δ13.6
Δ11.2
Δ5.4
Δ1.9 25
not studied
not studied as a cohort
21.0 months
PFS
9.3 months
PFS
Chemotherapy 6 months
GOG2135
OCEANS6
Phase 3
N=337
N=242 5 10 15
Δ3.4
Δ4.0
8.4
10.4
13.8
12.4
N=377
8.8
11.8
Δ3.0
MITO16B7
HR 0.628
HR 0.27
HR 0.45
HR 0.48
HR 0.18
HR 0.54
N=202
HR 0.51
HR 0.30
N=203
HR 0.23
Treatment Placebo
PFS, progression free survival; BRCA, breast cancer gene; gBRCAmut, germline breast cancer gene mutated
1. Mirza MR, et al. N Engl J Med 2016;375: ; 2. Ledermann J, et al. Lancet Oncology 2014;15: ; 3. Pujade-Lauraine E, et al. Lancet Oncology 2017;18: ;
4. Coleman RL, et al. Lancet 2017;390: ; 5. Coleman et al. Lancet Oncology 2017;18: ; 6. Aghajanian C, et al. J Clin Oncol 2012;30:
7. Pignata S, et al. J Clin Oncol 2018;36:(suppl; abstr 5506).

6. Standard practice maintenance strategies in ovarian cancer
Anti-angiogenesis
PARP inhibitors

8. The evidence: ENGOT-OV16 / NOVA
Recurrent ovarian, fallopian tube or primary peritoneal cancer following CR or PR to second-line or later platinum-based chemotherapy (N=553)
gBRCAmut (N=203)
2:1 Randomisation
Non-gBRCAmut (N=350)
2:1 Randomisation
Niraparib 300 mg QD
Placebo QD
Niraparib 300 mg QD
Placebo QD
Endpoint assessment
Endpoint assessment
Primary endpoint: PFS
Radiologic disease progression
Clinical signs and symptoms and increasing CA-125
Increasing CA-125 and additional diagnostic tests OR
Progression measured by:
BRCA, breast cancer gene; PFS, progression free survival; ENGOT, European Network for Gynaecological Oncological Trial groups; gBRCAmut, germline BRCA mutation
Mirza MR, et al. N Engl J Med 2016;375:

9. Stratification factors well balanced
gBRCAmut
Non-gBRCAmut
Characteristic
Niraparib (N=138)
Placebo (N=65)
Niraparib (N=234)
Placebo (N=116)
Time to progression after penultimate platinum therapy, N (%)
6 to <12 months
54 (39.1)
26 (40.0)
90 (38.5)
44 (37.9) 
≥12 months
84 (60.9)
39 (60.0)
144 (61.5)
72 (62.1)
Best response to most recent platinum therapy, N (%)
Complete response
71 (51.4)
33 (50.8)
117 (50.0)
60 (51.7)
Partial response*
67 (48.6)
32 (49.2)
56 (48.3)
Prior bevacizumab use, N (%)
Yes
33 (23.9)
17 (26.2)
62 (26.5)
30 (25.9) No
105 (76.1)
48 (73.8)
172 (73.5)
86 (74.1)
*42 patients had at least one tumour lesion >2 cm at baseline per IRC radiological review
Almost 50% of the patients had only achieved a PR after their most recent platinum regimen
Approximately 25% of the patients had received prior bevacizumab
gBRCA, germline breast cancer gene mutation; PR, partial response
Mirza MR, et al. N Engl J Med 2016;375:

10. PFS in the gBRCAmut cohort
Niraparib (N=138)
Placebo
(N=65)
Median PFS, months
21.0
5.5
HR=0.27
95% CI 0.17, 0.41
P<0.001
100 80 60 40 20
PFS (%) 24 4 8 12 16
Median PFS 5.5 months
Niraparib
Median PFS 21.0 months
Placebo
Time (months)
gBRCA, germline breast cancer gene mutation; PFS, progression free survival; HR, hazard ratio
Mirza MR, et al. N Engl J Med 2016;375:

11. PFS in non-gBRCAmut cohort
Non-gBRCAmut overall
Niraparib (N=234)
Placebo
(N=116)
Median PFS, months
9.3
3.9
HR=0.45
95% CI 0.34, 0.61
P<0.001
100 80 60
Median PFS 9.3 months
Median PFS 3.9 months
PFS (%) 40
Niraparib 20
Placebo 4 8 12 16 20 24
Time (months)
gBRCA, germline breast cancer gene mutation; PFS, progression free survival; HR, hazard ratio
Mirza MR, et al. N Engl J Med 2016;375:

12. Niraparib offers efficacy regardless of prior chemotherapy* response
1.0
gBRCAmut cohort
1.0
Non-gBRCAmut cohort
Niraparib/All
Niraparib/PR
Placebo/All
Placebo/PR
0.8
0.8
0.6
0.6
Progression-free survival probability
Progression-free survival probability
0.4
0.4
0.2
0.2
0.0
0.0 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24
Time since randomisation (months)
Time since randomisation (months)
PR to last platinum
Overall (N=203)
PFS HR† (95% CI)
0.24 (0.131–0.441)
0.27 (0.173–0.410)
PR to last platinum
Overall (N=203)
PFS HR† (95% CI)
0.35 ( )
0.45 ( )
*Last platinum-based chemotherapy; †Niraparib versus placebo.
CI, confidence interval; gBRCAmut, germline breast cancer gene mutation; HR, hazard ratio; PFS, progression-free survival; PR, partial response
Mirza MR, et al. Presented at American Society of Clinical Oncology; June 2-6, 2017; Chicago, Illinois

13. Number of patients on treatment in the NOVA trial
Treatment arm
Number of patients on treatment, N (%)
0–3 months
3 months–1 year
1–2 years
2–4 years
Niraparib
367 (100.0%)
298 (81.2%)
143 (39.0%)
69 (18.8%)
Placebo
179 (100.0%)
145 (81.0%)
31 (17.3%)
10 (5.6%)
Mirza MR, et al. IGCS 2018.

14. Other PARPi maintenance therapy study designs
Study 191 (Phase II)
Patients
gBRCA1, sBRCA, BRCA wild type
Platinum-sensitive recurrent high-grade serous ovarian cancer
At least two prior lines of platinum therapy
CR or PR to most recent platinum therapy
Olaparib
400 mg BID
N=136
Primary endpoint
Investigator-assessed
PFS R
1:1
N=265
Placebo BID
N=129
SOLO-22 (Phase III)
Patients
BRCA1/2 mutation
Platinum-sensitive high-grade endometrioid or serous ovarian cancer
At least two prior lines of platinum therapy
CR or PR to most recent platinum therapy
Olaparib
300 mg BID
N=196
Primary endpoint
Investigator-assessed
PFS R
2:1
N=295
Placebo
N=99
ARIEL33 (Phase III)
Patients
High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers
≥2 prior lines of platinum-based treatments
Sensitive to penultimate platinum
Responding to most recent platinum (CR or PR)
CA-125 within normal range
No restriction on size of residual tumour
Rucaparib
600 mg BID
N=375
Primary endpoint
Investigator-assessed PFS in molecularly defined HRR gene status subgroups
BRCAmut
HRD
ITT R
2:1
N=564
Placebo
N=189
BID, twice daily; BRCA, breast cancer gene; CR, complete response; HRR, homologous recombination repair; ITT, intention to treat; PFS, progression free survival;
PR, partial response; R, randomisarion; gBRCA, germline breast cancer gene; sBRCA, somatic breast cancer gene; OC, ovarian cancer
1. Ledermann J, et al. Lancet Oncol 2014;15: Pujade-Lauraine E, et al. Lancet Oncol 2017;18:
3. Coleman RL, et al. Lancet 2017;390:

15. Published PFS results in maintenance therapy studies
Anti-angiogenesis
BRCA status not determined
PARP inhibition
gBRCA patients
PARP inhibition
non-gBRCA patients
21.0 months
PFS
9.3 months
PFS
Chemotherapy 6 months
Chemotherapy 6 months
GOG2135
OCEANS6
Phase 3
N=337
N=242 5 10 15
Δ3.4
Δ4.0
8.4
10.4
13.8
12.4
N=377
8.8
11.8
Δ3.0
MITO16B7
Chemotherapy 6 months 21
N=138
9.3
Phase 3
NOVA1
N=234
HR 0.628
HR 0.27
HR 0.45
5.5
N=65
Δ15.5
3.9
Δ5.4
N=116
11.2
N=74
7.4
N=57
Phase 2
Study 192
HR 0.48
HR 0.18
4.3
N=62
Δ6.9
HR 0.54
5.5
Δ1.9
N=61
N=202
Phase 3
SOLO23
5.5
N=80
19.1
N=196
HR 0.51
not studied
Δ13.6
N=203
HR 0.30
Phase 3
ARIEL34
16.6
N=130
5.4
N=66
not studied as a cohort
HR 0.23
Δ11.2 5 10 15 20 25 5 10 15 20
Treatment Placebo
PFS, progression free survival; BRCA, breast cancer gene; gBRCAmut, germline breast cancer gene mutated
1. Mirza MR, et al. N Engl J Med 2016;375: ; 2. Ledermann J, et al. Lancet Oncology 2014;15: ; 3. Pujade-Lauraine E, et al. Lancet Oncology 2017;18: ;
4. Coleman RL, et al. Lancet 2017;390: ; 5. Coleman et al. Lancet Oncology 2017;18: ; 6. Aghajanian C, et al. J Clin Oncol 2012;30:
7. Pignata S, et al. J Clin Oncol 2018;36:(suppl; abstr 5506).

16. Not indicated as maintenance therapy yet
PARP inhibitors as maintenance therapy: where do we stand in sensitive relapsed ovarian cancer?
Niraparib
Olaparib
Rucaparib
Maintenance treatment of adult patients with high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer regardless of BRCA status
Not indicated as maintenance therapy yet
Maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer
Europe
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer regardless of BRCA status
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer regardless of BRCA status
Maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer regardless of BRCA status
United States
ENGOT-OV16 / NOVA1
Study 192
SOLO-23
ARIEL34
Key trials
ZEJULA™ [package insert]. Waltham, MA: TESARO, Inc.; 2017; ZEJULA™ [product information] London, UK: TESARO, UK Ltd.; 2017 LynparzaTM [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017; LynparzaTM [product information]. Cheshire, UK: AstraZeneca UK Limited; 2017; Rubraca® (rucaparib) [package insert]. Boulder, CO: Clovis Oncology, Inc: 2017; “Clovis Oncology’s rucaparib significantly improved progression-free survival in all ovarian cancer patient Populations Studied in Phase 3 ARIEL3 maintenance treatment trial”; news release, Available at: Accessed 7 August 2017
BRCA, breast cancer gene
1. Mirza MR, et al. N Engl J Med 2016;375:2154–64; 2. Ledermann J, et al. Lancet Oncol 2014;15: ; 3. Pujade-Lauraine E, et al. Lancet Oncol 2017;18: ; 4. Coleman RL, et al. Lancet 2017;390:

17. PARP inhibitors in first-line maintenance

18. Maintenance olaparib in patients with newly diagnosed BRCAmut advanced ovarian cancer: SOLO-1 trial
Olaparib 300 mg PO bid up to 2 years* or to
progression
Placebo bid up to 2 years* or to progression R
2:1
N=260
N=131
N=391
Newly diagnosed stage III-IV ovarian, primary peritoneal, or fallopian tube cancer
High-grade serous or endometrioid histology
Only patients with documented deleterious BRCA mutation
Stage III: 1 optimal debulking attempt
Stage IV: biopsy and/or 1 upfront or interval debulking
In CR or PR at end of frontline platinum-based chemotherapy
Olaparib met primary endpoint of progression-free survival in women with BRCAmut advanced ovarian cancer; Median PFS 13.8 vs NR (investigator assessed) [HR 0.3]
Therefore, with this information in mind make sense to extend the use of PARP inh as maintenance to the first-line therapy when the patients have already received 1 previous line of platinum.
The first trial addressing this question was the SOLO1. SOLO-1 is a phase 3 randomized, double blinded trial that enrolled patients with newly diagnosed BRCA-mutated high grade serous or endometrioid, Stage III or IV who have achieved a Partial or Complete response after Platinum based chemotherapy. Patients were randomized in a two ta one Olparib/ Placebo for 2 years or progression whichever occurs first.
but the importance of this study is whether time-limited olaparib therapy significantly improves OS, or just delays progression without influencing OS.
Study treatment continued until disease progression
Patients with no evidence of disease at 2 years stopped treatment
Patients with a partial response at 2 years could continue treatment
Primary endpoint: Investigator-assessed PFS by RECIST V1,1
Secondary endpoints:
OS, PFS2, best ORR, health-related quality of life by TOI of the FACT-O, TFST, TSST, and safety and tolerability
ClinicalTrials.gov. NCT
Moore K. ESMO LBA7_PR.
Moore K, et al. N Engl J Med 2018; DOI: /NEJMoa
*At investigators’ discretion
bid, twice daily; BRCAmut, breast cancer gene mutation; CR, complete response; FACT-O, functional assessment of cancer therapy; HR, hazard ratio; NR, non-responder; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PR, partial response; TOI, trial outcome index; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy

19. Key Secondary Endpoints
PRIMA / ENGOT-OV26/GOG-3012: Phase 3 trial of niraparib maintenance treatment in patients with advanced ovarian cancer following response on front-line platinum-based chemotherapy
High-grade Stage III or IV ovarian cancer (all comers) and achieved a CR or PR following front-line platinum-based chemotherapy
Stratification factors
Neoadjuvant chemotherapy administered: Yes or No
Best response to 1st platinum therapy: CR or PR
HRD status: positive or negative/not determined
2:1
Niraparib 300 mg daily
Placebo
Daily
Enrolment completed June 2018 (N=733)
Results expected end 2019
Endpoint assessment
The second one is the , PRIMA trial is an ongoing study of maintenance niraparib or placebo following therapy of patients with stage III or stage IV disease following surgery and chemotherapy. It includes a broader group of women including those without a BRCA mutation
ClinicalTrials.g
ov Identifier: NCT
413 AND 207
Primary
Endpoint
Hierarchical Testing for PFS (radiologic, central review)
· PFS in HRD pos population (HR 0.5)
· PFS in ITT population (HR 0.65)
Key Secondary Endpoints
Overall survival | Patient-reported outcomes (FOSI, EQ-5D-5L, EORTC-QLQ-30, EORTC-QLQ-OV28) | Safety & Tolerability | PFS2 | Time to CA-125 progression
ClinicalTrials.gov. NCT
CR, complete response; EORTC-QLQ-30, European Organisation for Research and Treatment of Cancer; EORTC-QLQ-OV28, EORTC–Ovarian Cancer Module; EQ-5D-5L, European QoL five-dimension five-level questionnaire; FOSI, FACIT ovarian cancer symptom index; HR, hazard ratio; HRD, homologous recombination deficiency; ITT, intention to treat; PFS, progression free survival; PK, pharmacokinetic; PR, partial response; QoL, quality of life

20. Stratification factors
FIRST: Phase 3, randomised, placebo-controlled comparison of platinum-based therapy with TSR-042 and niraparib vs. standard of care as first-line treatment
Concurrent bevacizumab use
BRCA/HRD status
Disease burden: Stage III with residual disease <1 cm (yes or no)
Stratification factors
Newly diagnosed stage III/IV advanced ovarian cancer
Cycle 1: Carboplatin + paclitaxel ± bevacizumab
Randomisation
Estimated enrolment: =~720 to 960
Treatment
21days cycle
x 5 cycles
Carboplatin + Paclitaxel
+ Placebo (TSR-042)
Carboplatin + Paclitaxel
+ Placebo (TSR-042)
Carboplatin + Paclitaxel
+ TSR-042
+/- Bevacizumab
Maintenance
Up to 3 years
Placebo (TSR-042) + Placebo (Niraparib)
Placebo (TSR-042) + Niraparib
TSR Niraparib
Gonzalez-Martin et al. ESMO Poster Figure 1 and Study Assessments PROs
+/- Bevacizumab (i.e., maintenance doublets and triplets)
Adaptive design anticipates evolving first-line standard of care: double-placebo maintenance arm may be transitioned to niraparib maintenance for BRCAmut (pending SOLO-1 success) and BRCAwt (pending PRIMA success) patients over time
Primary Endpoint
PFS by investigator-assessment per RECIST v1.1 criteria
Key Secondary Endpoints
Overall Survival
PFS by BICR
HRQoL
Safety & Tolerability
PFS by irRECIST
BRCA, breast cancer gene; BRCAmut, BRCA mutation; BRCAwt, BRCA wild-type; HRD, homologous recombination deficiency; PFS, progression-free survival; RECIST, response evaluation
criteria in solid tumours; BICR, blinded independent central review; irRECIST, immune-related response criteria in solid tumours; HRQoL, health-related quality of life; OS, overall survival
1. Accessed ; 2. TESARO, Inc. Data on File.

21. Take home points
PARP inhibitors are effective as maintenance therapy in germline BRCA mutated and platinum-sensitive ovarian cancer
Long-term efficacy has been demonstrated with niraparib
Niraparib offers effective maintenance therapy regardless of BRCA mutation status
PARP inhibitors are also effective in 1st-line maintenance in gBRCA (SOLO-1)
PRIMA will provide data in non-gBRCA
Future combinations of PARP inhibitors with other targeted agents may bring us closer to cure