|Ahead of print
Olaparib, a new hope for ovarian cancer
Zarka Samoon, Adnan Abdul Jabbar
Department of Oncology, Aga Khan University Hospital, Karachi, Pakistan
|Date of Submission||01-Jul-2019|
|Date of Decision||10-Mar-2019|
|Date of Acceptance||25-Mar-2019|
|Date of Web Publication||08-Jul-2020|
Department of Oncology, Aga Khan University Hospital, Karachi
Source of Support: None, Conflict of Interest: None
Ovarian cancer is the most common cause of death among gynecologic cancers and has a cure rate of less than 40% in women. Around 70% of women present with advanced disease, with a 5-year survival of 46.5%. There is an unmet need of therapies which can improve the survival rates.
Approximately 14.1%–28.3% of patients with newly diagnosed ovarian cancer have BRCA 1/2 mutation., This prevalence is said to be higher in those with platinum-sensitive disease. These tumors are deficient in homologous recombination repair (HRD) and are dependent on base excision repair pathway which is mediated by poly(adenosine diphosphate–ribose) polymerase (PARP) enzyme. Homologous recombination is restoration of DNA to the original form and nonhomologous recombination does not, hence making it error-prone.
Over the past few years, the development of PARP inhibitors has been of major importance in the management of ovarian cancer. PARP inhibitors are drugs that inhibit DNA repair thereby resulting in death of tumor cells. They do this in various ways. First, they prevent base excision repair, which leaves single-stranded breaks without recovery and increase the chance of cell for a second DNA damage., They may halt homologous recombination and increase nonhomologous joining. Such drugs are used to treat tumors that have defects in DNA repair such as tumors that have BRCA1 and BRCA2 mutations. We now know that in addition to germ-line BRCA mutations, HRD may also occur by somatic mutation, methylation of BRCA1 gene, and mutation of other genes. This possibly explains the efficacy of PARP inhibitors in high-grade serous platinum-sensitive ovarian cancer without germline BRCA mutation.
Olaparib was initially investigated to treat, and later was assessed as a maintenance therapy, at the outset after recurrent disease, and later after first-line therapy.
| » Olaparib as Treatment|| |
Olaparib, the first PARP inhibitor, was approved in December 2014 by Food and Drug Administration (FDA) for treatment of patients with germline BRCA-mutated ovarian cancer who had received two to three prior lines of therapy. This was based on objective response rate of 34% and median response duration of 7.9 months in the patient population in a phase III study by Kaufmann et al.
| » Olaparib as Maintenance in Recurrent Disease|| |
Historically, ovarian cancer is associated with a short disease-free interval after achieving remission. The median progression-free survival after first and second relapses has been reported to be 10.2 and 6.2 months, respectively. To continue having disease in remission, PARP inhibitors were tested as a second-line maintenance therapy. In the SOLO2/ENGOT-Ov-21 trial, olaparib was compared with placebo in patients with platinum-sensitive relapsed BRCA-mutated high-grade serous ovarian cancer as a second-line maintenance therapy. This led to a 13.6-month improvement in progression-free survival with no detrimental effect on quality of life. In phase II, P19 study, olaparib was associated with better progression-free survival irrespective of BRCA mutation status; however, on subsequent analysis of BRCA, those with germline mutation had the most benefit. Similarly in a study by Mirza et al., niraparib, a PARP 1/2 inhibitor, showed better progression-free survival when compared with placebo. Based on these data, both FDA and European Medicines Agency have approved olaparib as a maintenance therapy for recurrent high-grade ovarian cancer irrespective of BRCA status.
| » Olaparib as Maintenance After first-line Therapy|| |
In patients with advanced ovarian cancer who are in remission after first-line chemotherapy, the use of pazopanib or paclitaxel resulted in median improvement in progression-free survival of 5.6 and 7 months, respectively. This was associated with significant toxicity and no improvement in overall survival. In ICON7 and GOG 128, addition of bevacizumab to chemotherapy resulted in a modest 4-month improvement in progression-free survival in the high-risk group only (those with >1 cm residual disease and stage IV disease). However, when compared with the chemotherapy-only arm, this regimen was associated with slight decrease in quality of life. In view of impressive disease control with olaparib in the second-line setting, this drug was tested in the first line in SOLO1 trial. In this study, olaparib was compared with placebo as a maintenance treatment in BRCA-mutated women after partial or complete clinical response with platinum-based chemotherapy. Olaparib was associated with 70% lower risk of disease progression or death. The study reported the median time to first subsequent therapy or death to be 51.8 and 15.1 months with olaparib and placebo, respectively.
Generally, women with ovarian cancer are in first remission for around 1.5 years. For these women, 51.8 months of median chemotherapy-free time is a remarkable achievement. Historically, olaparib has been associated with side effects which are tolerable and do not impair the quality of life. The more common side effects are nausea, vomiting, fatigue, and anemia.
Can olaparib be used as first-line maintenance therapy in women without BRCA mutation? When used as a second maintenance therapy, the difference in progression-free survival has been of around 4 months in BRCA-nonmutated patients in the P19 study and the study by Mirza et al., Extrapolating from these previous data and thinking of a 4-month disease control, the answer for now would be no. This could perhaps be answered in future studies.
| » Future Studies of Olaparib|| |
Olaparib versus chemotherapy is being assessed for recurrent disease in the treatment setting in the SOLO3 (NCT02282020) trial. Various randomized trials are comparing a combination of olaparib with vascular endothelial growth factor receptor inhibitors such as bevacizumab and cediranib as maintenance after first line and recurrent disease in PAOLA-1 (NCT02477644) and ICON9 (NCT03278717), respectively. The oncology community awaits the unfolding of this exciting story.
| » References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30.
Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al
. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012;30:2654-63.
Dann RB, DeLoia JA, Timms KM, Zorn KK, Potter J, Flake DD, 2nd
, et al
. BRCA1/2 mutations and expression: Response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol 2012;125:677-82.
Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, et al
. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917.
El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res 2003;31:5526-33.
Patel AG, Sarkaria JN, Kaufmann SH. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 2011;108:3406-11.
Bryant HE, Petermann E, Schultz N, Jemth AS, Loseva O, Issaeva N, et al
. PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. Embo J 2009;28:2601-15.
Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al
. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011;12:852-61.
Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, 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;21:4257-61.
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al.
Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244–50.
Hanker LC, on behalf of the AGO, group Gs, Loibl S, on behalf of the AGO, group Gs, et al
. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol 2012;23:2605-12.
Friedlander M, Gebski V, Gibbs E, Davies L, Bloomfield R, Hilpert F, 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. Lancet Oncol 2018;19:1126-34.
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, 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;15:852-61.
Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al
. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154-64.