In this E-Learning module, the author explains phenotypic features of BRCA-mutated ovarian cancer, the mechanisms of repair of DNA damage, and the increased sensitivity of BRCA-positive tumours to PARP inhibition (PARPi). There is an explanation of tests used to assess for PARPi activity and how maintenance strategies have led to a change in management of women with ovarian cancer.
The author explains PARPi activity in women with BRCA-mutated and non-BRCA-mutated recurrent high grade serous ovarian cancer after a response to platinum-based therapy using a maintenance strategy, shows results from Study 19 BRCA- and non-BRCA-mutated subset analysis, outcomes by somatic or germline BRCA mutation, findings from SOLO-2 study of maintenance olaparib in women with BRCA-mutated platinum-sensitive recurrent ovarian cancer, findings from NOVA, ARIEL-3 and NORA studies with maintenance niraparib and rucaparib in BRCA-mutated platinum-responsive recurrent ovarian cancer, and looks into survival data and long-term responders.
The author then provides an overview of the results from SOLO3 study of olaparib monotherapy versus chemotherapy in women with BRCA-mutated recurrent ovarian cancer, the results of ARIEL4 study and reasons why progression-free survival not always translates into an overall survival benefit. After looking into rechallenge with chemotherapy in women with BRCA mutations recurring after SOLO2, the author goes into explanation of potential mechanisms for PARP resistance.
The next chapter is devoted to safety profile of different PARPi, dose reductions and discontinuation due to side effects, principles of management of PARPi toxicity, analysis of incidence of MDS/AML with PARPi in recurrent ovarian cancer, quality-of-life issues, and time without symptoms and toxicity.
In the following chapter, the author explains the introduction of maintenance with a PARPi in front-line treatment of women with high-grade ovarian cancer, provides overview of results from SOLO1 study, then the results from PAOLA- 1 study in tBRCA-mutated subpopulations receiving bevacizumab with or without olaparib, the findings in BRCA-mutated populations in PRIMA study with niraparib and the ATHENA-mono study with rucaparib. The toxicities and tolerability of treatment is discussed.
The next part of the module is devoted to maintenance PARPi beyond BRCA mutation in women with platinum-responsive recurrent ovarian cancer. The author also touches trials combining PARPi with immune checkpoint inhibitors with or without bevacizumab in front-line treatment. The final part of the module is devoted to providing the relevant algorithms and recommendations from the ESMO Clinical Practice Guidelines.
Jonathan Ledermann has reported:
Financial Interests:
Advisory Board, Speaker Fees, Personal: AstraZeneca, Clovis Oncology, GSK.
Advisory Board, Personal: Artios Pharma, Eisai, Merck/MSD, VBL Therapeutics, Bristol Myers Squibb, Nuvation, Ellipses, Immunogen, Miltenyi, Novocure, Immagene.
Invited Speaker, Personal, Speaker Fees: Neopharm.
Other, Personal, Independent Data Monitoring Committee: Mersana, Sutro Bio.
Research Grant, Institutional, Clinical Research University: AstraZeneca, MSD/Merck.
Non-Financial Interests:
European Society of Gynaecological Oncology, Leadership Role, Vice President ( 2019-2021).
ESMO, Officer, Chair Gynaecological Clinical Practice Guidelines.
Other:
Sage Publishing, Other, Associate Editor: Therapeutic Advances in Medical Oncology.
