1. Long-term Follow-up of Olaparib Maintenance Monotherapy in Platinum-Sensitive Serous Ovarian Cancer
CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3 - June 7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

2. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: Background
Olaparib: potent, oral PARP inhibitor
Traps PARP at damaged DNA, blocking base-excision repair and results in collapse of replication forks, accumulation of double-strand breaks in DNA[1]
Currently FDA approved for pts with BRCA-mutated ovarian cancer after ≥ 3 lines of chemotherapy
Phase II randomized, double-blind Study 19 showed significant improvement in PFS, TFST, and TSST in pts with ovarian cancer receiving olaparib maintenance monotherapy vs placebo; greatest benefit in pts with BRCA- mutation[2,3]
Overall: Median PFS (olaparib vs placebo) 8.4 vs 4.8 mos (HR: 0.35, P < .0001)
BRCA-mutant: Median PFS (olaparib vs placebo) 11.2 vs 4.3 mos (HR: 0.18, P < )
Current report is third interim analysis of OS in Study 19[4]
HRR, homologous recombination repair; PARP, poly ADP ribose polymerase; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy or death
1. Murai J, et al. Cancer Res. 2012;72: Ledermann J, et al. New Engl J Med. 2012;366: Ledermann J, et al. Lancet Oncol. 2014;15:
4. Ledermann JA, et al. ASCO Abstract 5501.
Slide credit: clinicaloptions.com

3. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: Study Design
Platinum-sensitive, recurrent high grade serous ovarian cancer; ≥2 prior platinum-based regimens with CR/PR to most recent platinum-based therapy
(N = 265)
Olaparib
400 mg BID, capsules
(n = 136)
Treatment until disease progression
Placebo
BID, capsules
(n = 129)
Primary endpoint: PFS (RECIST 1.0)
Secondary endpoints: OS, safety, tolerability
Exploratory endpoints: time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST)
Current report: descriptive updated OS analysis at 77% data maturity
Study 19 not designed to evaluate OS with statistical significance
OS P values deemed nominal for descriptive analysis
Type 1 error rate for subgroup analyses with no pre-specified rules
BID, twice daily; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy or death.
Slide credit: clinicaloptions.com
Ledermann JA, et al. ASCO Abstract 5501.

4. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: OS
OS*, Overall Study Population† (N = 265)
Olaparib
(n = 136)
Placebo
(n = 129)
Deaths, n (%)
94 (69)
109 (84)
Median OS, mos
29.8
27.8
HR: 0.73 (95% CI ); Nominal P = ‡
OS*, BRCAm Subgroup† (n = 136)
Olaparib
(n = 74)
Placebo
(n = 62)
Deaths, n (%)
47 (64)
48 (77)
Median OS, mos
34.9
30.2
HR: 0.62 (95% CI: ); Nominal P = ‡
OS*, BRCAwt Subgroup† (n = 118)
Olaparib
(n = 57)
Placebo
(n = 61)
Deaths, n (%)
43 (75)
56 (92)
Median OS, mos
24.5
26.6
HR: 0.83 (95% CI: ); Nominal P = .037
*Cox proportional hazards analysis; †Data maturity 77% for overall population, 70% for BRCAm, and 84% for BRCAwt at cut-off September 30, 2015; ‡Does not meet criterion for statistical significance (P < .0095)
Slide credit: clinicaloptions.com
Ledermann JA, et al. ASCO Abstract 5501.

5. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: OS
Restricted means analysis performed because of insufficient evidence to dismiss the proportional hazards assumption for OS[1,2]
Difference in mean survival strengthens olaparib OS advantage
BRCAm patients demonstrated greatest OS advantage
No inconsistency between OS data for somatic BRCAm subgroup and OS data for BRCAm, germline BRCAm, or overall population, however, conclusions limited by sample size (n = 20) OS
Overall study population
(N = 265)
BRCAm subgroup
(n = 136)
Olaparib
Placebo
(n = 129)
(n = 74)
(n = 62)
Restricted mean OS, mos
40.1
34.9
44.3
36.9
Difference in restricted mean OS, mos (95% CI)
5.2 (-0.8 to 11.2)
7.4 (-1.1 to 16.0)
1. Grambsch P, et al. Biometrika. 1994;81: Anderson PK, et al. Lifetime Data Anal. 2004;10: Ledermann JA, et al. ASCO Abstract 5501.
Slide credit: clinicaloptions.com

6. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: TFST by BRCA Subgroup
TFST, BRCAm Subgroup* (n = 136)
Olaparib
(n = 74)
Placebo
(n = 62)
TFST events, n (%)
53 (72)
59 (95)
Median TFST, mos
15.6
6.2
HR: 0.32 (95% CI: ); P <
TFST, BRCAwt Subgroup* (n = 118)
Olaparib
(n = 57)
Placebo
(n = 61)
TFST events, n (%)
47 (82)
60 (98)
Median TFST, mos
12.9
6.9
HR: 0.45 (95% CI: ); P =
TFST, time to first subsequent therapy.
*Maturity 82% for BRCAm and 91% for BRCAwt
Slide credit: clinicaloptions.com
Ledermann JA, et al. ASCO Abstract 5501.

7. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: TSST by BRCA Subgroup
TSST, BRCAm Subgroup* (n = 136)
Olaparib
(n = 74)
Placebo
(n = 62)
TSST events, n (%)
52 (70)
59 (90)
Median TSST, mos
22.0
15.3
HR: 0.41 (95% CI: ); P =
TSST, BRCAwt Subgroup* (n = 118)
Olaparib
(n = 57)
Placebo
(n = 61)
TSST events, n (%)
47 (82)
59 (97)
Median TSST, mos
17.0
14.7
HR: 0.63 (95% CI: ); P =
TSST, time to second subsequent therapy or death.
14 pts with BRCAm disease from placebo arm (23%) received post- discontinuation PARP inhibitor treatment
*Maturity 79% for BRCAm and 90% for BRCAwt
Slide credit: clinicaloptions.com
Ledermann JA, et al. ASCO Abstract 5501.

8. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: Long-term Tx Exposure
Median follow-up: 5.9 yrs
15 patients (11%) still receiving olaparib
8 BRCAm
7 BRCAwt
1 patient (< 1%) still receiving placebo (BRCAm)
Patients who received olaparib for ≥ 5 years
Overall population: 13%
BRCAm subgroup: 15%
BRCAwt: 12%
Slide credit: clinicaloptions.com
Ledermann JA, et al. ASCO Abstract 5501.

9. Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: Safety
Overall safety population: no new safety findings[1,2]
3 cases of MDS/AML (unchanged since 2012 report): 2 cases in olaparib arm (57 mos and 10 mos on treatment),1 case in placebo arm (44 mos)
Rate of common AEs (anemia, fatigue, nausea, vomiting) in pts receiving olaparib ≥ 2 yrs consistent with overall population; most initially reported during first 2 yrs[1,2]
Adverse Event, %
Overall (N = 265)
Treatment ≥ 2 yrs (n = 37)
Olaparib
(n = 136)
Placebo
(n = 128)
(n = 32)
(n = 5)
Any AE 97 93 94
100
Any grade ≥3 AE 43 22 47 20
Dose reductions due to AE 25 4
Discontinuation due to AE 6 2 9
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
1. Ledermann J, et al. New Engl J Med. 2012;366: Ledermann J, et al. Lancet Oncol. 2014;15: Ledermann JA, et al. ASCO Abstract 5501.
Slide credit: clinicaloptions.com

10. Olaparib vs Placebo in Serous Ovarian Cancer: Conclusions
OS advantage in pts with platinum-sensitive ovarian cancer who received olaparib maintenance vs placebo in Study 19 (HR: 0.73)
OS advantage most evident in BRCAm patients with a HR of 0.62
Criterion for statistical significance (P < .0095) not met at this analysis
Substantially prolonged TFST and TSST in olaparib arm, with greatest benefit seen in BRCAm pts
Long-term exposure to olaparib unprecedented
13% of all pts, including 15% of BRCAm pts, received 5 or more years of maintenance olaparib
No new safety findings during 3 years of additional follow-up since previous analysis
TFST, time to first subsequent therapy; TSST, time to second subsequent therapy or death.
Slide credit: clinicaloptions.com
Ledermann JA, et al. ASCO Abstract 5501.

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