Virtual Journal Club Ovarian Cancer Reference Slides Platinum-Sensitive Recurrent Ovarian Cancer: Making the Most of Emerging Targeted Therapies Mansoor R. Mirza, MD Copenhagen University Hospital Rigshospitalet Copenhagen, Denmark Discussants: Ignace Vergote, MD, PhD University Hospitals Leuven Leuven, European Union
Recurrent Ovarian Cancer 80% of women with ovarian cancer relapse on first-line treatment with platinum-based chemotherapy 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 nonchemotherapeutic 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.
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 XRCC1 Lig3 PNK Polß 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 Probability of Progression-Free Survival Olaparib Placebo Hazard ratio, 0.35 (95% CI, 0.25-0.49) P <.001 Months Since Randomization Ledermann J, et al. N Engl J Med. 2012;366:1382-1392.
PARP Inhibitors in Ovarian Cancer PARP inhibitor Route Target Current status in ovarian cancer Olaparib (AZD2281) 1 PO PARP-1, PARP-2, PARP-3 Veliparib (ABT-888) 2 PO PARP-1, PARP-2 Approved as maintenance therapy for recurrent, platinum-sensitive, BRCA mutated ovarian cancer Phase II trial complete; phase III trial ongoing Rucaparib (CO338, AGO14699 PO PARP-1, and PF01367338) 3 PARP-2, PARP-3 Niraparib (MK4827) 4 PO PARP-1, PARP-2 Talazoparib (BMN 673) 5 PO PARP-1, PARP-2 Phase II trial complete; phase III trial ongoing Phase III trial completed 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 Germline BRCA Mutant (gbrca mut) Non Germline BRCA Mutant Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. 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 P <.001 21.0 months 5.5 months Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.
PFS: Germline BRCA Mutation Negative P <.001 9.3 months 3.9 months Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.
PFS: Germline BRCA Mutation Negative, HRD Positive P <.001 12.9 months 3.8 months Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.
Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. PFS Subgroup Analysis
Secondary Efficacy Endpoints 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 Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.
Adverse Events Treatment-emergent grade 3/4 adverse events occurring in 5% of patients *There are no grade 5 events. AML, acute myeloid leukemia; MDS, myelodysplastic syndrome Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.
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