Virtual Journal Club

Ovarian Cancer

Platinum-Sensitive Recurrent Ovarian Cancer:

Making the Most of Emerging Targeted Therapies

Discussants:

Mansoor R. Mirza, MDCopenhagen University Hospital

Rigshospitalet

Copenhagen, Denmark

Ignace Vergote, MD, PhDUniversity Hospitals Leuven

Leuven, European Union

Reference Slides

Recurrent Ovarian Cancer

• Patients relapsing after >6 months are treated

with subsequent lines of platinum-based

therapy until resistance or death

– Successive lines of treatment associated

with lower response to treatment, increase

in tumor burden, and increase in

cumulative drug toxicity

– Median overall survival (OS) after first

recurrence is 2-3 years

• Maintenance therapy with bevacizumab or

olaparib remains the only non-

chemotherapeutic option in this setting

Hennessey BT, et al. Lancet. 2009;374(9698):1371-1382. Hanker LC, et al. Ann Oncol. 2012;23:2605-2612. National Comprehensive Cancer Network.

NCCN Clinical Practice Guidelines. Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed: December 1, 2016.

80% of women with ovarian cancer relapse on first-line treatment

with platinum-based chemotherapy

Lig3XRCC1

PolßPNK

Poly (ADP-Ribose) Polymerase (PARP)

• PARP plays a key role in the repair of DNA single-strand breaks through

the base excision repair pathway

• Binds directly to sites of DNA damage and generates large, branched

chains of poly (ADP-ribose) polymers on multiple target proteins

• Recruits other DNA repair enzymes

Plummer ER, et al. Clin Cancer Res. 2007;13:6252-6256. Farmer H, et al. Nature. 2005;434:917-921.

BRCA and PARP

• BRCA genes are critical for DNA damage repair and cells with

defective BRCA genes are more susceptible to DNA-damaging

therapy, including PARP inhibition

• In cells that are BRCA-1 and BRCA-2 deficient in the presence of a

PARP inhibitor, there is a marked decrease in the ability of cells to

repair themselves and, as a result, the concentration of the cells

diminishes over time

• Having both PARP inhibition as well as an abnormality in homologous

repair results in greater cell death

• PARP inhibitors have demonstrated activity as maintenance therapy in

recurrent, platinum-sensitive ovarian cancer with BRCA mutations or

deficiencies in homologous recombination (HRD)

Plummer ER, et al. Clin Cancer Res. 2007;13:6252-6256. Farmer H, et al. Nature. 2005;434:917-921.

PARP Inhibitor Mechanism of Action

Iglehart JD, et al. N Engl J Med. 2009;361(2):189-191.

PARP Inhibitors in Ovarian Cancer

Ledermann J, et al. N Engl J Med. 2012;366:1382-1392.

Months Since Randomization

Hazard ratio, 0.35 (95% CI, 0.25-0.49)

P < .001

Pro

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Olaparib

Placebo

PARP Inhibitors in Ovarian Cancer

PARP inhibitor Route Target Current status in ovarian cancer

Olaparib (AZD2281)1 PO PARP-1,

PARP-2,

PARP-3

Approved as maintenance therapy for recurrent,

platinum-sensitive, BRCA mutated ovarian cancer

Veliparib (ABT-888)2 PO PARP-1,

PARP-2

Phase II trial complete; phase III trial ongoing

Rucaparib (CO338, AGO14699

and PF01367338)3

PO PARP-1,

PARP-2,

PARP-3

Phase II trial complete; phase III trial ongoing

Niraparib (MK4827)4 PO PARP-1,

PARP-2

Phase III trial completed

Talazoparib (BMN 673)5 PO PARP-1,

PARP-2

Phase II trial ongoing

1. Ledermann J, et al. N Engl J Med. 2012;366:1382-1392. 2. Coleman RL, et al. Gynecol Oncol. 2015;137(3):386-391. 3. Drew Y, et al. Br J Cancer.

2016;114(7):723-730. 4. Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. 5. Meehan RS, et al. Gynecol Oncol Res Pract. 2016;3:3.

BRCA Wild-Type Ovarian Cancer

• Most studies of PARP inhibitors in ovarian cancer have focused

on patients with germline BRCA mutations and/or HRD

• For patients without these mutations, platinum chemotherapy

followed by watchful waiting is the only available treatment option

• Niraparib, a potent, oral, selective PARP 1-2 inhibitor, has

demonstrated antitumor activity in both BRCA mutated and

BRCA mutation-negative high-grade serous ovarian cancer

Meehan RS, Chen A. Gynecol Oncol Res Pract. 2016;3:3.

Niraparib Early Phase Clinical Trial

• Efficacy of niraparib was evaluated in a phase I dose

escalation trial in sporadic cancer, including ovarian cancer

• Overall response rate (ORR) was 40% in BRCA mutated

ovarian cancer and 50% in platinum-sensitive BRCA mutants

• 3 of 4 (75%) patients with platinum-sensitive ovarian cancer

receiving the recommended dose of 300 mg responded

• Median PFS was 63 weeks both in patients with BRCA

mutations and those without BRCA mutations

Sandhu SK, et al. Lancet Oncol. 2013;14(9):882-892. Michie CO, et al. J Clin Oncol. 2013;suppl: Abstract 2513.

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

ENGOT-OV16 NOVA Trail

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

Germline BRCA Mutant (gBRCA mut) Non Germline BRCA Mutant

P <

.05

P <

.05;

P <

.05

ENGOT-OV16 NOVA Trail: Patient Demographics and Baseline Characteristics

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

PFS: Germline BRCA Mutation

21.0 months

5.5 months

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

P < .001

PFS: Germline BRCA Mutation Negative

9.3 months

3.9 months

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

P < .001

PFS: Germline BRCA Mutation Negative, HRD Positive

12.9 months

3.8 months

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

P < .001

PFS Subgroup Analysis

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

Secondary Efficacy Endpoints

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

Chemotherapy-free interval

• Germline BRCA mutation: HR 0.26 (22.8 months vs 9.4 months; 95% CI: 0.169, 0.414; P < .0001

• Non germline BRCA mutation: HR 0.50 (12.7 months vs 8.6 months; 95% CI: 0.370, 0.666; P < .0001

Time to first subsequent treatment

• Germline BRCA mutation: HR 0.31 (21.0 months vs 8.4 months; 95% CI: 0.205, 0.481; P < .0001

• Non germline BRCA mutation: HR 0.55 (11.8 months vs 7.2 months; 95% CI: 0.412, 0.721; P < .0001

Progression-free survival 2 (data are immature)

• Germline BRCA mutation: HR 0.48 (25.8 months vs 19.5 months; 95% CI: 0.280, 0.821; P = .0062

• Non germline BRCA mutation: HR 0.69 (18.6 months vs 15.6 months; 95% CI: 0.494, 0.964; P = .0293

Overall survival (data are immature)

• <20% patients death in either treatment arm; HR 0.73 (95% CI, 0.480 to 1.125; P = .1545

Adverse Events

Treatment-emergent grade 3/4 adverse events occurring in ≥5% of patients

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

*There are no grade 5 events.

AML, acute myeloid leukemia; MDS, myelodysplastic syndrome

Dose Adjustments Due to Treatment-Emergent Adverse Events

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

Conclusions• There is an unmet need in platinum-sensitive, recurrent ovarian cancer for treatments that

prolong survival and improve patient quality-of-life

• The currently approved PARP inhibitor, olaparib, improves outcomes in patients with BRCA

mutations and/or HRD deficiencies

• In a randomized, double-blind, placebo-controlled phase III trial, maintenance treatment with

the selective PARP 1/2 inhibitor niraparib significantly improved PFS in all patient subgroups

examined, regardless of BRCA mutation or HRD status

– gBRCA mut: HR 0.27

– No gBRCA mut: HR 0.45

– No gBRCA mut, HRD positive: HR 0.38

• Hematologic laboratory abnormalities were the most common adverse events and were

managed through dose reduction

– The 1.4% rate of MDS/AML is similar to other PARP inhibitors currently used in this

setting.

• Niraparib represents a novel approach to management of recurrent, platinum-sensitive

ovarian cancer and opens the door for PARP inhibitor therapy in patients without

BRCA mutations