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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.

  1. First-line Maintenance
  2. Second-line Maintenance
  3. Monotherapy

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

PFSHRD 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

  1. Moore K, Colombo N, Scambia G et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018; 379.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.

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