Ovarian cancer is the leading cause of gynecologic cancer–related death in the United
States. Historically, studies have demonstrated that ovarian cancer is a heterogeneous
disease with several patient and oncologic characteristics, including BRCA status and residual disease at surgery, known to be predictive of clinical outcomes.
However, during the last decade, the discovery and approval of bevacizumab and poly(adenosine
diphosphate-ribose) polymerase inhibitors have moved the frontline treatment paradigm
beyond platinum-doublet therapy for women with advanced ovarian cancer. Subsequently,
investigators have sought to assess the therapeutic efficacy of these agents in women
who are considered “high” risk and “low” risk to determine which patients may benefit
the most from aggressive therapy and in whom additional treatment may be avoided.
We reviewed historic and contemporary definitions of “high-risk” and “low-risk” ovarian
cancer and how this has been incorporated into the subset analyses of randomized,
clinical trials of therapeutic agents, including bevacizumab and poly(adenosine diphosphate-ribose)
polymerase inhibitors. Next, we provided an in-depth discussion of landmark trials
for frontline maintenance therapy with bevacizumab and/or poly(adenosine diphosphate-ribose)
polymerase inhibitors, focusing on the impact of treatment efficacy according to a
“high-risk” and “low-risk” paradigm. Furthermore, we highlighted that recent data
have challenged this dichotomous classification, notably from the Gynecologic Oncology
Group-0218, ICON7, SOLO-1, and PAOLA-1 trials. Although some studies have suggested
that certain populations of women with advanced ovarian cancer may have a more favorable
prognosis and be considered “low risk,” the risk of progression and death remains
unacceptably high in all women. Furthermore, in many cases, those considered the lowest
risk have the most treatment benefit from maintenance therapy with poly(adenosine
diphosphate-ribose) polymerase inhibitors and/or bevacizumab. From these data, we
have advocated that virtually all women with advanced ovarian cancer are high risk
and that the use of our most effective therapies in the frontline setting holds promise
for potentially curing more patients. Lastly, we critically discuss the practice of
using subanalyses in clinical trials, with emphasis that although this practice is
important for hypothesis generation, caution must be taken before accepting findings
from subanalyses as actual treatment effects.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to American Journal of Obstetrics & GynecologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 7-30
- Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer.Int J Gynaecol Obstet. 2006; 95: S161-S192
- Nomogram for predicting individual survival after recurrence of advanced-stage, high-grade ovarian carcinoma.Obstet Gynecol. 2019; 133: 245-254
- Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2018; 379: 2495-2505
- Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.N Engl J Med. 2019; 381: 2416-2428
- Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.N Engl J Med. 2019; 381: 2403-2415
- Incorporation of bevacizumab in the primary treatment of ovarian cancer.N Engl J Med. 2011; 365: 2473-2483
- Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer.J Clin Oncol. 2019; 37: 2317-2328
- Ascites predicts treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube and peritoneal cancers: an NRG Oncology/GOG study.Gynecol Oncol. 2015; 139: 17-22
- A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med. 2011; 365: 2484-2496
- Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.Lancet Oncol. 2015; 16: 928-936
- Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study.J Clin Oncol. 2007; 25: 3621-3627
- The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study.Gynecol Oncol. 1992; 47: 159-166
- Analysis of survivorship in high-risk patients treated on GOG-218.Gynecol Oncol. 2013; 130: e112-e113
- Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2021; 22: 620-631
- Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1274-1284
- Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.N Engl J Med. 2012; 366: 1382-1392
- Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 390: 1949-1961
- Niraparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2019; 381: 2391-2402
- Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1.Gynecol Oncol. 2021; 162: S25-S26
- 811MO Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1.Ann Oncol. 2020; 31: S613
- Ovarian cancer, version 2.2020, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2021; 19: 191-226
- Efficacy of maintenance olaparib for patients with newly diagnosed advanced ovarian cancer with a BRCA mutation: subgroup analysis findings from the SOLO1 trial.J Clin Oncol. 2020; 38: 3528-3537
- Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: subgroup analysis by risk in the phase III SOLO1 study.Int J Gynecol Cancer. 2020; 30 (A76–7): 392
- Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: a review.Gynecol Oncol. 2021; 162: 482-495
- Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.Ann Oncol. 2019; 30: 551-557
- A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer.J Clin Oncol. 2020; 38: 6003
- Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.J Clin Oncol. 2021; 39: 5514
- Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.Int J Cancer. 2020; 146: 439-448
Article Info
Publication History
Published online: May 28, 2022
Accepted:
May 24,
2022
Received in revised form:
May 13,
2022
Received:
November 10,
2021
Publication stage
In Press Journal Pre-ProofFootnotes
L.M.C reports no conflict of interest. D.M.O.M reports receiving personal fees (consulting and/or advisory boards) and funding for clinical research from AstraZeneca , Tesaro/GlaxoSmithKline [GSK], ImmunoGen , Ambry , Janssen/Johnson & Johnson , AbbVie , Regeneron , Amgen , Novocure , Genentech/Roche , Gynecologic Oncology Group Foundation , Iovance , Eisai , Agenus , Merck , Seagen , Mersana , Clovis , and Sumitomo Dainippon Pharma Oncology (Boston Biomedical Inc); funding from VentiRx , Array BioPharma , EMD Serono , Ergomed , Ajinomoto Inc , Ludwig Cancer Research , Stemcentrx , Cerulean Pharma Inc , Bristol Myers Squibb , TRACON Pharma , Yale University , New Mexico Cancer Care Alliance , INC Research , inVentiv Health Clinical , PRA Intl, GenMab ; and personal fees from Myriad Genetics, Tarveda Therapeutics, Novartis, Rubis, Elevar, Takeda, Toray, InxMed, Arquer Diagnostics, Roche Diagnostics MSA, Sorrento Therapeutics, Corcept Therapeutics, and Celsion Corporation. R.L.C. reports receiving grants and personal fees from Roche/Genentech, during the conduct of the study; grants and personal fees from AstraZeneca, Clovis, Roche/Genentech, GenMab, and Janssen; grants from Merck; and personal fees from Tesaro, Medivation, GamaMabs Pharma, Agenus, Regeneron, and OncoQuest, outside the submitted work. T.J.H. reports receiving personal fees for being a member of the Scientific Advisory Boards from Aravive, AstraZeneca, Caris, Clovis, Roche/Genentech, GSK, Merck, Eisai, and Seagen.
Identification
Copyright
© 2022 Published by Elsevier Inc.
