LETTER TO THE EDITOR
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|Year : 2020 | Volume
| Issue : 3 | Page : 346--347
Olaparib, a new hope for ovarian cancer
Zarka Samoon, Adnan Abdul Jabbar
Department of Oncology, Aga Khan University Hospital, Karachi, Pakistan
Department of Oncology, Aga Khan University Hospital, Karachi
|How to cite this article:|
Samoon Z, Jabbar AA. Olaparib, a new hope for ovarian cancer.Indian J Cancer 2020;57:346-347
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Samoon Z, Jabbar AA. Olaparib, a new hope for ovarian cancer. Indian J Cancer [serial online] 2020 [cited 2020 Oct 19 ];57:346-347
Available from: https://www.indianjcancer.com/text.asp?2020/57/3/346/289207
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.
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