Ovarian Cancer

Efficacy

PARP inhibitors have demonstrated efficacy in several settings for ovarian cancer, including as first- and second-line maintenance therapy following other treatments, and as monotherapy in advanced disease.

1. First-line maintenance

Only one trial has been reported to date in the first-line maintenance setting. The phase III SOLO1 trial of olaparib maintenance versus placebo was conducted in newly-diagnosed patients with BRCA mutations and a complete or partial response to cytoreductive surgery and platinum-based chemotherapy [1]. In the olaparib group, the rate of freedom from disease progression and from death at 3 years (investigator assessed) was significantly greater than placebo (60% vs 27%; HR: 0.30; 95% CI: 0.23─0.41; p<0.001); a sensitivity analysis showed that median progression-free survival was approximately 36 months longer in the olaparib group [1]. Median follow-up was 41 months (>3 years), providing crucial long-term outcome data for this novel treatment strategy [1].

2. Second-line maintenance

The three drugs currently approved in the maintenance setting in recurrent ovarian cancer (olaparib, niraparib and rucaparib) have similar efficacy following platinum-sensitive relapse in patients with germline BRCA mutations [2-5]. Progression-free survival benefit was greater in the context of germline or somatic BRCA mutations (HR 0.18–0.30 in the various studies), but patients with BRCA wild-type tumours also consistently derived a significant benefit from PARP inhibition ( HR 0.38–0.58 in various molecular subgroups). Compared with placebo, maintenance therapy with olaparib did not detrimentally affect health-related quality of life (HRQOL), and there were benefits seen in some other measures such as time without significant symptoms of toxicity (TWiST) and quality-adjusted progression-free survival (QAPFS) [6, 7]. Niraparib maintenance also did not impair QoL [4]

It is important to note that there were some important differences in BRCA status between the registration trials; in particular the SOLO2 study was restricted to patients with germline or somatic BRCA mutations, whereas NOVA, ARIEL-3 and Study 19 recruited patients both with and without BRCA mutations.

3. Monotherapy

In the monotherapy setting, a number of non-randomised phase II trials have been conducted. The progression-free survival attained using PARP inhibitors in these trials was comparable with other treatment options in heavily-pretreated, relapsed patients [8-11].

The trials used either investigator-assessed progression-free survival or investigator assessed response rate as primary endpoint; blinded independent central review was a secondary endpoint in some trials.

Click on each setting below to find out more on the key efficacy data from trials of PARP inhibitors in ovarian cancer.

Key efficacy data from trials of PARP inhibitors in ovarian cancer

First-line Maintenance Setting

Olaparib (tablets) versus placebo (SOLO1): Newly diagnosed, advanced ovarian cancer, g/s BRCA1/2mutations [1].
3-year PFS^*	60% vs 27%; HR: 0.30; 95% CI: 0.23─0.41; p<0.001
3-year PFS^†	69% vs 35%; HR: 0.28; 95% CI: 0.20─0.39; p<0.001
3-year PFS2	75% vs 60%; HR: 0.50; 95% CI, 0.35–0.72; p<0.001
^*Investigator assessed ^†Blinded independent central review g/s: germline or somatic mutations, PFS: Progression Free Survival, PFS2: Progression Free Survival 2

Second-line Maintenance Setting

Olaparib (capsules) vs placebo (Study 19): Platinum-sensitive, recurrent, high-grade serous [3, 4].
PFS^*– all patients	8.4 (7.4-11.5) vs 4.8 (4.0-5.5); HR 0.35 (95% CI 0.25-0.49); p<0.0001
PFS^* – BRCA mutation	11.2 (8.3-NC) vs 4.3 (3.0-5.4); HR 0.18 (95% CI 0.10–0.31); p<0.0001
PFS^* – BRCA WT	7.4 (5.5-10.3) vs 5.5 (3.7–5.6); HR 0.54 (95% CI 0.34–0.85); p=0.0075
OS – all patients	29.8 (26.9-35.7) vs 27.8 (24.9-33.7); HR 0.73 (95% CI 0.55-0.96) p=0.025
OS – BRCA mutation	34.9 (29.2-54.6) vs 30.2 (23.1-40.7); HR 0.62 (95% CI 0.41-0.94) p=0.025
OS – BRCA WT	24.5 (19.8-35.0) vs 26.6 (23.1-32.5); HR 0.83 (95% CI 0.55-1.24) p=0.37
Olaparib (tablets) vs placebo (SOLO2): Platinum sensitive, relapsed, germline or somatic BRCA1/2 mutations [5].
PFS^*	19.1 (16.3-25.7) vs 5.5 (5.2-5.8); HR 0.30 (95% CI 0.22-0.41) p<0.0001
PFS^†	30.2 (19.8-NC) vs 5.5 (4.8-5.6); HR 0.25 (95% CI 0.18-0.35) p<0.0001
TFST or Death	27.9 (22.6-NC) vs 7.1 (6.3-8.3); HR 0.28 (95% CI 0.21-0.38) p<0.0001
TTSP or Death	NR (24.1-NC) vs 18.4 (15.4-22.8); HR 0.50 (95% CI 0.34-0.72) p<0.0002
TSST or Death	Not reached (NC) vs 18.2 (15.0-20.5); HR 0.37 (95% CI 0.26-0.53) p<0.0001
Niraparib vs placebo (NOVA): Platinum-sensitive, relapsed [4].
PFS^† – gBRCA	21.0 vs 5.5; HR 0.27 (95% CI 0.17-0.41) p<0.001
PFS^† – Non gBRCA	9.3 vs 3.9; HR 0.45 (95% CI 0.34-0.61) p<0.001
PFS^† HRD+ve/Non-gBRCA	12.9 vs 3.8; HR 0.38 (95% CI 0.24-0.59) p<0.001
PFS^† HRD-ve/Non-gBRCA	6.9 vs 3.8; HR 0.58 (95% CI 0.36-0.92) p=0.02
TFST – gBRCA	21.0 (17.5–NR) vs 8.4 (6.6–10.6); HR 0.31 (95% CI 0.21–0.48) p<0.001
TFST – Non gBRCA	11.8 (9.7–13.1) vs 7.2 (5.7–8.5); HR 0.55 (95% CI 0.41–0.72) p<0.001
PFS2 – gBRCA	25.8 (20.3–NR) vs 19.5 (13.3–NR); HR 0.48 (95% CI 0.28–0.82) p=0.006
PFS2 – Non gBRCA	18.6 (16.2–21.7) vs 15.6 (13.2–20.9); HR 0.69 (95% CI 0.49–0.96) p=0.03
Rucaparib vs control (ARIEL 3): Relapsed, platinum-sensitive high-grade, after ≥2 lines of previous therapy [2].
PFS^* – g/s BRCA	16.6 (13.4-22.9) vs 5.4 (3.4-6.7); HR 0.23 (95%CI 0.16-0.34), p<0.0001
PFS^† – g/s BRCA	26.8 (19.2-NR) vs 5.4 (4.9-8.1); HR 0.20 (95%CI 0.13-0.32), p<0.0001
PFS^* – HRD deficient	13.6 (10.9-16.2) vs 5.4 (5.1-5.6); HR 0.32, (95% CI 0.24–0.42), p<0.0001
PFS^† – HRD deficient	22.9 (16.2-NR) vs 5.5 (5.1-7.4); HR 0.34 (95%CI 0.24-0.47), p<0.0001
PFS^* (ITT)	10.8 (8.3-11.4) vs 5.4 (5.3-5.5); HR 0.36 (95%CI 0.30-0.45), p<0.0001
PFS^† (ITT)	13.7 (11.0-19.1) vs 5.4 (5.1-5.5); HR 0.35 (95%CI 0.28-0.45), p<0.0001
Unless otherwise indicated all data is in months (median, 95% CI). ^*Investigator assessed ^†Blinded independent central review g/s: germline or somatic mutations, ITT, intent-to-treat; NC: Non-calculable, NR: Not reached, OS: Overall Survival, PFS: Progression Free Survival, PFS2: Progression Free Survival 2, TFST: Time to First Subsequent Therapy, TTSP: Time to Second Progression, TSST: Time to Second Subsequent Therapy, WT: wild type.

Monotherapy Setting

Olaparib (capsules) (Study 42): gBRCA1/2 mutations, ≥3 lines of previous therapy [8].
PFS^* – all patients	6.7 (5.5-7.6)
PFS^* platinum-sensitive	9.4 (6.7-11.4)
PFS^* platinum-resistant	5.5 (4.2-6.7)
Rucaparib (ARIEL 2 and Study 10): s/gBRCA1/2 mutations, high-grade, ≥2 lines of previous therapy [12].
PFS^* platinum-sensitive	11.1 (7.3-12.8)
PFS^* platinum-resistant	5.3 (1.7-NR)
Unless otherwise indicated all data is in months (95% CI). ^*Investigator assessed g/s: germline or somatic mutations, PFS: Progression Free Survival.

References

Moore K, Colombo N, Scambia G et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018; 379.
Coleman RL, Oza AM, Lorusso D et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390: 1949-1961.
Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852-861.
Mirza MR, Monk BJ, Herrstedt J et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016; 375: 2154-2164.
Pujade-Lauraine E, Ledermann JA, Selle F et al. 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. Lancet Oncol 2017; 18: 1274-1284.
Friedlander M, Gebski V, Gibbs E et al. Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial. The Lancet Oncology 2018; 19: 1126-1134.
Ledermann JA, Harter P, Gourley C et al. Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer. British Journal Of Cancer 2016; 115: 1313-1320.
Domchek SM, Aghajanian C, Shapira-Frommer R et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol 2016; 140: 199-203.
Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244-250.
Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18: 75-87.
Kim G, Ison G, McKee AE et al. FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Clin Cancer Res 2015; 21: 4257-4261.
Oza AM, Tinker AV, Oaknin A et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol 2017; 147: 267-275.