NCCN Continuing Education
Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-24-011-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until October 10, 2025. PAs should only claim credit commensurate with the extent of their participation.
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/94873; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.
Release date: October 10, 2024; Expiration date: October 10, 2025
Learning Objectives:
Upon completion of this activity, participants will be able to:
• Integrate into professional practice the updates to the NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer
• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer
Disclosure of Relevant Financial Relationships
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Andrew Berchuck, MD, Panel Member
Sharon Robertson, MD, MPH, Panel Member
Shitanshu Uppal, MBBS, MBA, Panel Member
Frankie Jones, Guidelines Layout Specialist, NCCN
Emily Kovach, Guidelines Layout Specialist, NCCN
Lisa Hang, PhD, Oncology Scientist/Senior Medical Writer, NCCN
Swathi Ramakrishnan, PhD, Oncology Scientist/Medical Writer, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Deborah K. Armstrong, MD, Panel Chair, has disclosed serving as a scientific advisor for AstraZeneca Pharmaceuticals LP and GSK; and receiving grant/research support from AstraZeneca Pharmaceuticals LP and Eisai Inc.
Ronald D. Alvarez, MD, MBA, Panel Vice Chair, has disclosed serving as a scientific advisor for AstraZeneca Pharmaceuticals LP, GSK, and Myriad Genetic Laboratories, Inc.
Joyce Liu, MD, MPH, Panel Member, has disclosed receiving consulting fees from AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Daiichi-Sankyo Co., Eisai Inc., Genentech, Inc., GSK, and Zentalis.
Floor J. Backes, MD, Panel Member, has disclosed receiving consulting fees from AstraZeneca Pharmaceuticals LP, BioNTech, Clovis Oncology, Daiichi-Sankyo Co., Eisai Inc., EMD Serono, GSK, ImmunoGen, Inc., Merck & Co., Inc., and Myriad Genetic Laboratories, Inc.; receiving grant/research support from AstraZeneca Pharmaceuticals LP, Clovis Oncology, Eisai Inc., ImmunoGen, Inc., Merck & Co., Inc., Natera, Inc., and Tempus; and serving as a scientific advisor for AstraZeneca Pharmaceuticals LP, BioNTech, Clovis Oncology, Daiichi-Sankyo Co., Eisai Inc., EMD Serono, GSK, ImmunoGen, Inc., and Merck & Co., Inc.
Joshua Cohen, MD, Panel Member, has disclosed receiving consulting fees from and serving as a scientific advisor for ImmunoGen, Inc., and AstraZeneca Pharmaceuticals LP.
Rachel Grisham, MD, Panel Member, has disclosed receiving consulting fees from AstraZeneca Pharmaceuticals LP; and receiving honoraria from Cardinal Health, GSK, Myriad Genetic Laboratories, Inc., and Verastem.
Charles A. Leath III, MD, MSPH, Panel Member, has disclosed receiving grant/research support from AbbVie, Inc., Agenus, AstraZeneca Pharmaceuticals LP, Celsion, Corcept Therapeutics, GSK, Merck & Co., Inc.; receiving consulting fees from Celsion, GSK, and Merck & Co., Inc.; and serving as a scientific advisor for Pfizer Inc.
Lainie Martin, MD, Panel Member, has disclosed serving as a scientific advisor for Daiichi-Sankyo Co., ImmunoGen, Inc., and SUTRO Biopharma, Inc.
Daniela Matei, MD, Panel Member, has disclosed receiving consulting fees from CVS Health and GSK; and receiving grant/research support from PinotBio Inc., Eisai Inc., Acrivon Therapeutics, Shattuck Labs, and Merck & Co. Inc.
David S. Miller, MD, Panel Member, has disclosed receiving consulting fees from AbbVie, Inc., Agenus Inc., AstraZeneca Pharmaceuticals LP, Asymmetric Therapeutics, LLC, Boston Biomedical, Eisai Inc., EMD Serono, GSK, ImmunoGen, Inc., Incyte Corporation, iTeos Therapeutics, Inc., Karyopharm Therapeutics, Merck & Co., Inc., Myriad Genetic Laboratories, Inc., Novartis Pharmaceuticals Corporation, Novocure, Seagen Inc., and Tarveda Therapeutics; receiving grant/research support from Advaxis Inc., Advenchen Laboratories, LLC, Aeterna Zentaris Inc., Agenus Inc., Akeso, Inc., Aprea Therapeutics AB, AstraZeneca Pharmaceuticals LP, EMD Serono, ImmunoGen, Inc., Incyte Corporation, Janssen Pharmaceutica Products, LP, Karyopharm Therapeutics, Leap Therapeutics, Inc., Mateon Therapeutics, Inc., Merck & Co., Inc., Millennium Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, NVISION, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Syros Pharmaceuticals, TESARO, Inc., TRACON Pharmaceuticals, Inc., US Biotest, Inc., and Xenetic Biosciences, Inc.; and serving on the product/speakers bureau for Clovis Oncology and Genentech, Inc.
Lisa Barroilhet, MD, Panel Member, has disclosed serving as a scientific advisor for Merck & Co., Inc.
Andrea Wahner Hendrickson, MD, Panel Member, has disclosed receiving grant/research support from Amgen Inc., Aravive, Inc., AstraZeneca Pharmaceuticals LP, Harpoon Therapeutics, Inc., ProLynx, and TESARO, Inc.; and serving as a scientific advisor for Oxcia AB.
To view disclosures of external relationships for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Bristol Myers Squibb; Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Seagen. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc., Rahway, NJ, USA.
Overview
Epithelial ovarian cancer is the sixth most common cause of cancer mortality in females in the United States.1 Germline or somatic BRCA1/2 mutations are identified in 6% to 15% of patients with ovarian cancer.2,3 BRCA1 and BRCA2 are important components of the homologous recombination repair (HRR) pathway that can be triggered upon accumulation of DNA damage–mediated double-stranded breaks (DSBs).4,5 Loss of BRCA function causes HRR deficiency (HRD), resulting in dependence on other less efficient mechanisms of DNA repair and leading to accumulation of unrepaired DNA, genomic instability, and cell death.4,5
Poly-ADP ribose polymerase (PARP) enzymes have a multifaceted role in the sequence of events after DNA damage, one of which is to act as a scaffold to assemble components of HRR at the site of DSBs.6 PARP1 is the best characterized enzyme of the PARP enzyme family. Inhibiting PARP activity prevents assembly of repair components, including BRCA proteins, leading to accumulation of unrepaired DSBs that ultimately lead to cell death.6 Cells with germline or somatic BRCA mutations will already have inefficient repair processes due to HRD and are dependent on PARP-mediated repair, making these cells susceptible to death via inhibition of PARP activity. This sets the stage for exploiting synthetic lethality by using PARP inhibitors to cause cell death and therefore curtail tumor growth in a subset of patients with deleterious germline or somatic BRCA mutations.
PARP inhibitors, including olaparib, rucaparib, and niraparib, were widely studied in ovarian cancer and became established as maintenance treatment after frontline and recurrent platinum-based therapies and as monotherapy for BRCA-mutated or HRD disease. Long-term clinical data raised questions about the prolonged efficacy and safety of these agents in the recurrent setting. This resulted in company/FDA-initiated withdrawals for the monotherapy indications and restriction of PARP inhibitor maintenance in the recurrent setting to those patients with BRCA-mutated disease. These NCCN Guidelines Insights address the changing treatment landscape and provide a summary of current recommended PARP inhibitor use in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer.
PARP Inhibitors as Maintenance Therapy in First-Line Setting
Several clinical trials have examined the efficacy of PARP inhibitors as maintenance regimens post primary therapy, including the SOLO-1 trial that investigated 2 years maintenance olaparib (vs placebo) in patients with newly diagnosed advanced ovarian cancer harboring germline or somatic BRCA1/2 mutations.7,8 Patients with complete response (CR) or partial response (PR) after first-line platinum-based chemotherapy were included, whereas those who received bevacizumab as part of primary systemic therapy were excluded.7,8 After a median follow-up of approximately 41 months, patients receiving olaparib demonstrated a remarkable improvement in progression-free survival (PFS). The rate of freedom from disease progression and death at 3 years was 69% in those receiving olaparib compared with 35% in those receiving placebo (P<.001).7,8 Longer follow-up at 7 years showed that 67% of patients treated with olaparib compared with 46% of patients treated with placebo were still alive.9 Additionally, the time to first subsequent therapy was delayed in the olaparib arm compared with the placebo arm.9 Unlike SOLO-1, PAOLA-1 included patients with newly diagnosed high-grade serous ovarian cancer regardless of BRCA1/2 status and compared the combination of olaparib (up to 24 months)/bevacizumab with bevacizumab monotherapy in the maintenance setting.10 Although there was no statistically significant improvement in overall survival (OS) in the intent-to-treat (ITT) population, a clinically meaningful OS benefit was observed for those with HRD tumors; 5-year OS was 65.5% versus 48.4% and median OS was 75.2 versus 57.3 months with olaparib/bevacizumab treatment versus bevacizumab alone, respectively (hazard ratio [HR], 0.62; 95% CI, 0.45–0.85).10 Survival benefit was greatest in the BRCA-mutated subgroup (HR, 0.60; 95% CI, 0.39–0.93) but was also observed in the HRD-positive subgroup in the absence of somatic BRCA mutations (HR, 0.71; 95% CI, 0.45–1.13). The trial did not include an olaparib single-agent arm.
Other PARP inhibitors, niraparib and rucaparib, were investigated in different clinical trials around the same time. The PRIMA trial examined single-agent niraparib, for 3 years or until disease progression, as maintenance therapy for patients with advanced-stage disease who were in CR/PR after first-line platinum-based chemotherapy, and demonstrated a significant improvement in PFS with niraparib compared with placebo in the patients with HRD, with or without a BRCA1/2 mutation (21.9 vs 10.4 months; P<.001).11 In the ITT population, which included patients who had homologous recombination proficient (HRP) tumors, median PFS was 13.8 versus 8.2 months.11 In the HRD group, median PFS was 24.5 months for those receiving niraparib versus 11.2 months for the placebo arm. In the HRP population, median PFS was 8.4 months for those receiving niraparib versus 5.4 months for the placebo arm. The final OS analysis from PRIMA confirmed the PFS benefit reported in the initial analysis, but no difference in OS was observed between the niraparib maintenance or placebo arms in either the overall population or by HRD/BRCA status.12 In the PRIMA study about half of the patients in the placebo group received a PARP inhibitor in subsequent lines of therapy, which could compromise the ability to demonstrate improved OS. Similarly, single-agent maintenance rucaparib for up to 2 years demonstrated significant clinical benefit in those with HRD as well as the overall ITT population when compared with placebo in the ATHENA-MONO trial, which included patients regardless of BRCA or HRD status.13 In ARIEL3, 21% of patients in the rucaparib arm had a PFS of ≥2 years compared with 2% in the placebo arm. There was an association between the presence of BRCA or certain HRR mutations (RAD51C, RAD51D) and long-term PFS benefit from rucaparib.14 Niraparib in combination with bevacizumab for up to 3 years has also been studied in a single-arm phase II study, OVARIO, which reported that 62% of all patients, 76% of patients with HRD, 47% of patients with HRP tumors, and 56% of those with unknown homologous recombination status remained progression-free at 18 months.15
Results from these trials led to FDA approval of olaparib as monotherapy (for patients with a BRCA mutation) or in combination with bevacizumab (for patients with a BRCA mutation and/or HRD tumors) and of niraparib monotherapy as maintenance therapy for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have CR/PR following first-line platinum-based chemotherapy.16,17 Following FDA approvals, olaparib, olaparib/bevacizumab, and niraparib were initially added as first-line maintenance therapy options to the guidelines between 2019 and 2020. In 2023, rucaparib (which was previously FDA-approved for maintenance therapy in recurrent disease) was added as a monotherapy first-line maintenance option based on panel consensus. In 2024, niraparib/bevacizumab was added as a first-line maintenance therapy option for patients unable to tolerate olaparib. Neither of the latter 2 indications are currently FDA-approved.
The current recommendations for PARP inhibitors as first-line maintenance therapy post primary treatment of stage II–IV tumors (Figure 1) are based on (1) prior use of bevacizumab, (2) presence of germline or somatic BRCA1/2 mutations, and (3) CR/PR status after first-line treatment. The panel recognizes that the current clinical HRD tests are proxy measures of HRD and lack accuracy in fully predicting functional HRD. Nonetheless, the panel members recommend HRD testing for those patients without germline BRCA1/2 mutations, because HRD status may provide information on the magnitude of benefit of PARP inhibitor maintenance therapy in these patients. The median survival benefit is approximately 3 months in patients with HRP status, which comprise approximately half of all cases. Therefore, the panel considered the use of PARP inhibitors in patients who have HRP tumors to be of minimal benefit at present. Maintenance with bevacizumab + olaparib is a Category 1 option for patients with HRD tumors who have achieved CR/PR after completing bevacizumab-containing first-line therapy. Olaparib and niraparib monotherapy are Category 1 recommendations for those with germline or somatic BRCA1/2 mutations and who received first-line platinum-based chemotherapy without bevacizumab, whereas olaparib and niraparib monotherapy are Category 2A options for those who received bevacizumab as part of primary therapy.
Data regarding PARP inhibitor use in patients with stage II ovarian cancer is limited and it is unlikely that future trials of PARP inhibitors as maintenance therapy post primary treatment will address this question. Furthermore, diagnosis of stage II disease is rare, especially among patients who have undergone complete surgical staging. For these reasons, the NCCN panel decided that PARP inhibitor maintenance therapy options that are recommended for patients with stage III–IV disease (Figure 1) and who have completed first-line chemotherapy should also be considered for patients who have stage II disease. The NCCN Guidelines recommendations for maintenance options specifically apply to patients with high-grade serous or grade 2/3 endometrioid cancer types. Whether these maintenance therapies are appropriate for patients with less common epithelial ovarian cancer types (ie, carcinosarcoma, clear cell carcinoma, mucinous carcinoma, grade 1 endometrioid, and low-grade serous) has not been studied.
PARP Inhibitors as Maintenance Therapy for Recurrent Disease
The recommendations for PARP inhibitors as second-line maintenance therapy options have been updated based on the following studies and FDA indications. In 2017, the FDA approved niraparib and olaparib for maintenance therapy after response to platinum-based therapy for recurrent platinum-sensitive disease based on the results of 3 phase III randomized controlled trials: NOVA, SOLO-2, and Study 19. In 2018, the FDA approved rucaparib as maintenance therapy in recurrent disease.18 Subset retrospective nonanalytical analyses of several studies in recurrent disease for OS did not demonstrate a statistically significant improvement in OS with the use of PARP inhibitors as second-line maintenance therapy, and further raised the question whether there could be a negative impact in patients with wild-type BRCA. Therefore, the FDA approached manufacturers and requested that they voluntarily revise PARP inhibitor indications in the second-line maintenance therapy to restrict use to patients with germline/somatic BRCA-mutated cancers only. Following the FDA’s request, second-line maintenance indications were modified for all 3 PARP inhibitors: rucaparib is now limited to patients with germline or somatic BRCA mutations, niraparib is now limited to patients with germline BRCA mutations, and olaparib is now limited to patients with germline or somatic BRCA mutations.
The panel does not recommend bevacizumab and PARP inhibitor combination as a maintenance option in the recurrent disease setting. PARP inhibitor use is limited to those with BRCA1/2 mutations if not previously used (Category 1) or if disease did not progress during prior PARP inhibitor treatment (Category 2A) (Figure 2). The panel notes that these regimens significantly improve outcomes in patients with BRCA-mutated tumors and who are PARP inhibitor–naïve, suggesting that patients who most likely benefit from PARP inhibitors are those who receive them in the frontline setting. However, patients who have BRCA-mutated tumors who are PARP inhibitor–naïve and respond to platinum in the recurrent setting should still be offered a maintenance PARP inhibitor. For patients who have received prior PARP inhibitors, the panel recognizes that there are limited data in those who receive repeat PARP inhibitors as second-line maintenance therapy.
PARP Inhibitor Monotherapy for Recurrent Platinum-Sensitive/Resistant Disease
Initial results from trials utilizing PARP inhibitors in platinum-sensitive/resistant disease showed promising results. Early phase I/II trials demonstrated that olaparib is active in select patients with BRCA1/2 mutations and recurrent disease.19–21 The FDA approved olaparib in 2014 for patients with advanced ovarian cancer who have received ≥3 lines of chemotherapy and who carry a germline deleterious BRCA mutation.22,23 Based on early trial results and FDA approval, during the 2015 annual update the NCCN panel recommended single-agent olaparib as a recurrence therapy option for patients with advanced ovarian cancer (platinum-sensitive or platinum-resistant) who had received ≥3 lines of chemotherapy and a germline BRCA mutation. Trials assessing rucaparib and niraparib showed similar antitumor activity and rates of adverse events, which led to all the PARP inhibitors incorporated in the guidelines over the next 5 years as targeted therapy options for recurrent platinum-sensitive and resistant disease.24–26 During short-term follow-up, the common adverse events observed in those treated with PARP inhibitors included thrombocytopenia, neutropenia, and anemia.24,26 Until this point, there were no major concerns regarding the use of single-agent PARP inhibitors when given in the third or even fourth line of therapy in patients with recurrent disease.
However, the long-term efficacy and safety data on the use of PARP inhibitors as therapy for recurrent disease were not as complimentary as the initial data. At 70% data maturity in the ARIEL-4 trial, which compared rucaparib with chemotherapy, rucaparib treatment was not associated with improved OS in the ITT population.27,28 Although nonsignificant OS differences were observed in the recurrent platinum-sensitive disease, rucaparib use was associated with significantly worse OS in those with platinum-resistant disease.27,28 It is thought that the OS analysis was confounded due to >60% of patients from the control group crossing over to receive rucaparib. There were no additional safety concerns with regard to adverse events in patients treated with rucaparib at this point during the analysis. However, in June 2022, the company voluntarily withdrew rucaparib for treating patients with BRCA1/2-mutated ovarian cancer after ≥2 prior lines of chemotherapy, because no OS benefit was observed.29
Phase II studies of olaparib as monotherapy in advanced cancers with germline BRCA mutations showed initial promising results, with approximately 31% tumor response rates (CR/PR) in those with heavily pretreated ovarian cancer.30 SOLO-3 compared olaparib to physician’s choice single-agent nonplatinum chemotherapy in patients with germline BRCA mutations and recurrent high-grade platinum-sensitive ovarian cancer who had been treated with ≥2 lines of platinum-based chemotherapy.31 The initial study that conducted blinded independent central review showed that olaparib treatment resulted in statistically significant improvements in overall response rates and PFS.31 However, at final data cutoff analysis, there was no statistical difference in clinical responses, and OS was similar between the olaparib and chemotherapy groups.32 In August 2022, following the final analysis, the company voluntarily withdrew olaparib indication for the treatment of patients with germline BRCA1/2-mutated advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy.33 Subsequently, in September 2022, niraparib, which was approved for treatment of patients with HRD-positive advanced ovarian cancer who had been treated with ≥3 prior lines of chemotherapy, was also voluntarily withdrawn by the company for this indication.34
Based on these data and the FDA withdrawal announcements, the NCCN panel met and revised the recommendations for PARP inhibitor monotherapy for recurrent ovarian cancer. In a series of interim updates in 2022, the category of evidence and preference for rucaparib, niraparib, and olaparib was changed from Category 2A, Preferred regimen to Category 3, Other Recommended regimens for both platinum-sensitive and platinum-resistant disease (Figures 3 and 4).
Evolving Landscape of PARP Inhibitors
In a meta-analysis of 28 randomized control trials, the risk of hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), were higher in patients treated with long-term PARP inhibitors.35 Analysis of the PAOLA-1 trial at 5 years, showed that the rates of MDS, AML, aplastic anemia, and new primary malignancy incidence remained low and at a similar rate between the olaparib/bevacizumab and placebo/bevacizumab arms.10 The authors note that a higher proportion of patients in the placebo arm received subsequent PARP inhibitor therapy and could be a reason similar rates were observed between the 2 arms.10 Patients with BRCA mutation and prolonged PARP exposure (≥2 years) show increased risk of developing MDS and AML.14,36,37 Therefore, the panel urges caution when using PARP inhibitors as maintenance therapy for longer than 24 months, especially in the recurrence setting (Figure 2), and emphasizes the need for careful evaluation of risks and benefits when considering PARP inhibitor use in subsequent lines of therapy.
Summary and Conclusions
The panel recognizes that data relevant to subsequent lines of therapy cannot be extrapolated to the frontline setting. The NCCN panel recommendations for PARP inhibitors have been updated to align with the evolution of efficacy and safety profiles of these treatments as maintenance and single-agent regimens in select patients in both frontline and subsequent therapies.
References
- 2.↑
Alsop K, Fereday S, Meldrum C, 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;30:2654–2663.
- 3.↑
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609–615.
- 4.↑
Tutt A, Bertwistle D, Valentine J, et al. Mutation in BRCA2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J 2001;20:4704–4716.
- 5.↑
Moynahan ME, Chiu JW, Koller BH, Jasin M. BRCA1 controls homology-directed DNA repair. Mol Cell 1999;4:511–518.
- 6.↑
Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 2014;25:32–40.
- 7.↑
Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495–2505.
- 8.↑
Banerjee S, Moore KN, Colombo N, et al. 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.
- 9.↑
DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol 2023;41:609–617.
- 10.↑
Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol 2023;34:681–692.
- 11.↑
Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391–2402.
- 12.↑
Monk BJ, Barretina-Ginesta MP, Pothuri B, et al. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from PRIMA/ENGOT-OV26/GOG-3012 trial. Ann Oncol. Published online August 21, 2024. doi:10.1016/j.annonc.2024.08.2241
- 13.↑
Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol 2022;40:3952–3964.
- 14.↑
O’Malley DM, Oza AM, Lorusso D, et al. Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian carcinoma. Gynecol Oncol 2022;167:404–413.
- 15.↑
Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab. Gynecol Oncol 2022;166:219–229.
- 16.↑
Arora S, Balasubramaniam S, Zhang H, et al. FDA approval summary: olaparib monotherapy or in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer. Oncologist 2021;26:e164–172.
- 17.↑
US Food & Drug Administration. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. Accessed December 9, 2022. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer
- 18.↑
US Food & Drug Administration. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. Accessed December 9, 2022. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-rucaparib-maintenance-treatment-recurrent-ovarian-fallopian-tube-or-primary-peritoneal
- 19.↑
Gelmon KA, Tischkowitz M, Mackay H, 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;12:852–861.
- 20.↑
Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010;376:245–251.
- 21.↑
Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 2010;28:2512–2519.
- 23.↑
Kim G, Ison G, McKee AE, 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;21:4257–4261.
- 24.↑
Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017;18:75–87.
- 25.↑
Balasubramaniam S, Beaver JA, Horton S, et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer. Clin Cancer Res 2017;23:7165–7170.
- 26.↑
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375:2154–2164.
- 27.↑
Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol 2022;23:465–478.
- 28.↑
Kristeleit R, Shapiro GI, Burris HA, et al. A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clin Cancer Res 2017;23:4095–4106.
- 29.↑
Important Prescribing Information: rucaparib for treatment of BRCA- mutated ovarian cancer after 2 or more chemotherapies is voluntarily withdrawn in the US. Accessed August 22, 2022. Available at: https://clovisoncology.com/pdfs/US_DHCPL_final_signed.pdf
- 30.↑
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244–250.
- 31.↑
Penson RT, Valencia RV, Cibula D, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol 2020;38:1164–1174.
- 32.↑
Penson R, Valencia RV, Colombo N, et al. Final overall survival results from SOLO3: phase III trial assessing olaparib monotherapy versus non-platinum chemotherapy in heavily pretreated patients with germline BRCA1 - and/or BRCA2-mutated platinum-sensitive relapsed ovarian cancer (026). Gynecol Oncol 2022;166:S19–20.
- 33.↑
AstraZeneca. Dear Health Care Provider Letter (Olaparib) - September 2023. Accessed December 9, 2022. Available at: https://www.lynparzahcp.com/content/dam/physician-services/us/590-lynparza-hcp-branded/hcp-global/pdf/solo3-dhcp-final-signed.pdf
- 34.↑
GSK. Dear Health Care Provider Letter (Niraparib) - November 2022. Accessed December 9, 2022. Available at: https://www.zejulahcp.com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US/pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20November%202022.pdf
- 35.↑
Morice PM, Leary A, Dolladille C, et al. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. Lancet Haematol 2021;8:e122–134.
- 36.↑
Poveda A, Floquet A, Ledermann JA, et al. 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.
- 37.↑
Coleman RL, Oza A, Lorusso D, et al. O003/#557 Overall survival results from ARIEL3: a phase 3 randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma. Int J Gynecol Cancer 2022;32:A3–4.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN CATEGORIES OF PREFERENCE
Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation).
All recommendations are considered appropriate.
Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
The NCCN Guidelines® Insights highlight important changes in the NCCN Guidelines® recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding the content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.