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      Saturday, September 23, 2023
      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
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      CME / ABIM MOC

      Maintenance Therapy for Ovarian Cancer: Practical Considerations for Community Practice

      • Authors: Ursula Matulonis, MD; Lyndsay Willmott, MD; Terry Jannuzzo
      • CME / ABIM MOC Released: 3/28/2019
      • THIS ACTIVITY HAS EXPIRED FOR CREDIT
      • Valid for credit through: 3/28/2020, 11:59 PM EST
      Start Activity

      Target Audience and Goal Statement

      This activity is intended for community practice-based oncologists and gynecologic oncologists who manage patients with ovarian cancer.

      The goal of this symposium is to improve the knowledge of community-based oncologists on the most up-to-date clinical trial data on poly (ADP-ribose) polymerase (PARP) inhibitors and the antiangiogenic agent bevacizumab in maintenance therapy for patients with advanced ovarian cancer to increase their competence and confidence in the optimal use of maintenance therapy in these patients.

      Upon completion of this activity, participants will:

      • Have increased knowledge regarding the
        • Clinical trial safety and efficacy data evaluating PARP inhibitors and antiangiogenics as maintenance therapy in ovarian cancer
        • Practical approaches to overcoming barriers to utilizing maintenance therapy in the management of advanced ovarian cancer in community practice
      • Have greater competence related to
        • Identifying patients with advanced ovarian cancer who are candidates for maintenance therapy
      • Demonstrate greater confidence in their ability to
        • Communicate effectively with patients about maintenance therapy for advanced ovarian cancer in order to involve them in shared decision-making

      Disclosures

      As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

      Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

      Faculty

      • Ursula Matulonis, MD

        Professor of Medicine
        Harvard Medical School
        Director and Chief, Division of Gynecologic Oncology
        Brock-Wilson Family Chair
        Dana-Farber Cancer Institute
        Boston, Massachusetts

        Disclosures

        Disclosure: Ursula Matulonis, MD, has disclosed the following relevant financial relationships:
        Served as an advisor or consultant for: 2X Oncology, Inc.; Geneos Therapeutics, Inc.; Immunogen, Inc.; Mersana Therapeutics, Inc.
        Received grants for clinical research from: Merck & Co., Inc.

      • Terry Jannuzzo

        Ovarian Cancer Survivor/Advocate
        Dutchess County, New York

        Disclosures

        Disclosure: Terry Jannuzzo has disclosed the following relevant financial relationships:
        Patient assistance program: AstraZeneca Pharmaceuticals LP

      • Lyndsay Willmott, MD

        Gynecologic Oncologist
        Arizona Oncology
        Phoenix, Arizona

        Disclosures

        Disclosure: Lyndsay Willmott, MD, has disclosed the following relevant financial relationships:
        Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP
        Served as a speaker or a member of a speakers bureau for: Clovis Oncology; Merck & Co., Inc.; TESARO, Inc.

      Editor

      • Lisa Brauer, PhD

        Scientific Director, Medscape, LLC

        Disclosures

        Disclosure: Lisa Brauer, PhD, has disclosed no relevant financial relationships.

      • Andrew D. Bowser, ELS, CHCP

        Scientific Director, Medscape, LLC

        Disclosures

        Disclosure: Andrew D. Bowser, ELS, CHCP, has disclosed the following relevant financial relationships:
        Spouse served as a speaker for Shire and as an advisor or consultant for ALK, CSL Behring, and Pharming.

      CME Reviewer

      • Amy Bernard, MS, BSN, RN-BC, CHCP

        Lead Nurse Planner, Medscape, LLC

        Disclosures

        Disclosure: Amy Bernard, MS, BSN, RN-BC, CHCP, has disclosed no relevant financial relationships.

      Peer Reviewer

      This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

      Accreditation Statements

      Medscape

      Interprofessional Continuing Education

      In support of improving patient care, Medscape, LLC 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.

        For Physicians

      • Medscape, LLC designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

        Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.25 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

        Medscape, LLC staff have disclosed that they have no relevant financial relationships.

        Contact This Provider

      For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

      Instructions for Participation and Credit

      There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

      This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test.

      Follow these steps to earn CME/CE credit*:

      1. Read the target audience, learning objectives, and author disclosures.
      2. Study the educational content online or printed out.
      3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming.

      You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker.

      *The credit that you receive is based on your user profile.

      CME / ABIM MOC

      Maintenance Therapy for Ovarian Cancer: Practical Considerations for Community Practice

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      • Maintenance Therapy for Ovarian Cancer: Practical Considerations for Community Practice

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          Slide 1.

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        • Best Practices for Maintenance Therapy in Recurrent Ovarian Cancer

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            Slide 3.

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          • Overview of Maintenance Therapy for Recurrent Ovarian Cancer[1]

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            • Overview of Maintenance Therapy for Recurrent Ovarian Cancer (cont)[1-4]

              • The niraparib and rucaparib studies enrolled all comers (ie, BRCA and non-BRCA mutated cancers)

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            • Overview of Maintenance Therapy for Recurrent Ovarian Cancer (cont)[1-7]

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              • Maintenance Strategies for Platinum-Sensitive Recurrent Ovarian Cancer[2-7]

                • There are inherent differences in how maintenance is defined in the context of poly (ADP-ribose) polymerase (PARP) inhibitor therapy and bevacizumab therapy
                  • PARP maintenance is added at the end of chemotherapy (not concomitantly) to avoid overlapping bone marrow suppression
                  • Bevacizumab maintenance therapy trials have looked at chemotherapy alone versus chemotherapy-bevacizumab combined followed by bevacizumab maintenance
                • This can make it challenging for patients to discern between regimens and maintenance approaches

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              • Important Differences Between PARP Inhibitor and BEV Maintenance Trials[2-7]

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                • BEV Maintenance Studies[6,7]

                  • OCEANS showed a progression-free survival (PFS) improvement of about 4 months for added bevacizumab, with no difference in overall survival
                  • GOG-0213 also showed a PFS improvement approaching 4 months, and overall survival that was trending toward significance or just reaching significance, depending on analysis

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                • The OCEANS Trial[6]

                  • OCEANS trial: all subgroups examined showed improvement in PFS

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                • The OCEANS Trial (cont)[6]

                  • However, overall survival really was not improved with bevacizumab added

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                • The GOG213 Trial[7]

                  • Neither prior bevacizumab nor the treatment-free interval influenced outcomes on bevacizumab

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                • BEV-Related Toxicities in BEV Maintenance Trials[6,7]

                  • Significant adverse events were more frequent when bevacizumab was added to chemotherapy

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                • Additional Lower Grade Toxicities of BEV in the OCEANS Trial[6]

                  • Additional lower-grade toxicities are present with bevacizumab, including arthralgias, cough, dysphonia, and epistaxis

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                  Slide 14.

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                • Biochemical Properties of PARP Inhibitors[14-16]

                  • The 3 PARP inhibitors that are now FDA-approved in ovarian cancer have different half-lives and different biochemical structures as well

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                  Slide 17.

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                • Predictors of Response to PARP Inhibitors: Number of Prior Lines of Therapy and Platinum Sensitivity[18]

                  • Overall response rates declined with increasing platinum resistance and more lines of treatment

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                • Randomized Trial of Maintenance Olaparib in Platinum-Sensitive High-Grade Serous Relapsed Ovarian Cancer - Study 19: Design[1]

                  • Study 19 was a seminal study in this area

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                  Slide 21.

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                • Study 19: PFS[1,19]

                  • The median PFS in the overall population was approximately 4 months, but in a retrospective subgroup analysis looking at BRCA-mutated cancers, there was a more than 7-month improvement

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                  Slide 22.

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                • SOLO2/ENGOT-OV21:Study Design[3]

                  • SOLO2 included only patients whose cancers have an underlying BRCA mutation

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                • SOLO2/ENGOT-OV21:PFS in BRCA-Mutated, Platinum-Sensitive Disease[3]

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                  • Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer[2]

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                    • ENGOT-OV16/NOVA: Primary Analysis of PFS in Patient Subsets[2]

                      • In the 3 primary efficacy populations, median PFS is significantly prolonged with niraparib vs placebo
                      • For the germline BRCA-positive patients, median PFS was 5.5 months in the placebo arm, similar to what was seen in the SOLO2 trial

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                    • ENGOT-OV16/NOVA: Niraparib Effect on PFS in Patients Without Germline BRCAm Most Notable in HRD-Positive Subset[2]

                      • Subgroup populations also showed improvement in PFS albeit to a lesser degree compared with the initial populations

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                      Slide 28.

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                    • ARIEL3: Investigator-Assessed PFS[4]

                      • In all 3 subgroups the addition of rucaparib vs placebo at maintenance generated an improvement in median PFS
                      • As in previous studies, the BRCA-mutated groups appeared to derive the most benefit from a PARP inhibitor
                      • Median PFS of 5.4 months in the placebo group (BRCA mutant) was again quite similar to both SOLO2 and NOVA trials previously described

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                      Slide 31.

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                    • Summary of Phase 3 PARP Maintenance Studies[20]

                      • Given that the 3 available agents show comparable efficacy, treatment selection is based on the characteristics other than efficacy

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                      Slide 32.

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                    • PARP Inhibitor Characteristics Inform Treatment Choices

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                      • Challenge: Price of PARP Inhibitors[21]

                        • These PARP inhibitors have fairly similar cost per month (US$)
                        • Patient copays may be substantial
                        • Specific initiatives (eg, patient-assistance programs) may bring down the cost of PARP inhibitors

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                        Slide 34.

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                      • Special Considerations for Maintenance Therapy in Community Practice

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                          Slide 36.

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                        • BRCA Mutations and Cancer Risk[29]

                          • Risk of cancers among women with BRCA1/2 mutations is considerably elevated compared to the general population

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                          Slide 39.

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                        • NCCN Testing Guideline[30]

                          • While all women with ovarian cancer should be tested, unfortunately some patients are still falling through the cracks
                          • Some providers are still relying on older ideas that perhaps age and family history should be considered in the decision of whether or not to test

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                        • Limitations to Multigene Testing

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                          • Genetic Testing: Somatic Testing[32]

                            • Strategies for somatic testing have been debated
                            • Start with somatic testing may have financial advantages, but there is some lingering concern that some mutations could be missed

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                            Slide 45.

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                          • SOLO1: Olaparib Phase 3 Trial First-Line Maintenance Study, in Collaboration With the GOG - Study GOG 3004[34]

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                              Slide 48.

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                            • SOLO1: Investigator-Assessed PFS[34]

                              • PFS advantage was impressive and plateaued despite drug discontinuation
                              • Median PFS of only 13.8 months was observed in the placebo arm; some expected it would be longer

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                              Slide 49.

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                            • SOLO1: Investigator-Assessed PFS Subgroup Analysis[34]

                              • All subgroups had improvement in their PFS favoring olaparib

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                              Slide 50.

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                            • SOLO1: Most Common Grade 3/4 Toxicities[34]

                              • Toxicities in this trial are very similar to the toxicities in the recurrent setting
                              • The most common included gastrointestinal (GI) toxicities, bone marrow suppression and fatigue
                              • A fair number of patients in the placebo arms also experienced toxicities
                              • In general, patients did not have to come off of trial related to the toxicities

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                            • Key Grade 3/4 Toxicities From Phase 3 Maintenance Studies[2-4]

                              • Toxicities from maintenance studies show a very similar theme involving bone marrow suppression with anemia and thrombocytopenia, as well as GI toxicities including nausea and also fatigue
                              • Hypertension is a toxicity that was described in patients on niraparib
                              • There were some elevations in liver function tests (LFTs) described in the ARIEL3 trial for patients on rucaparib

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                            • Practical Considerations With PARP Inhibitors[16,15,14]

                              • There are some of the practical considerations that maybe can help you to decide which PARP would be appropriate for a particular patient,
                              • Both rucaparib and olaparib are metabolized via the CYP enzymes, whereas niraparib is metabolized via carboxyl esterases.
                              • Rucaparib has not had any important described drug-drug interactions, so there is no need to make any dose modifications or take patients off of other medications
                              • For olaparib, might need to consider reducing the dosage if patients are on concurrent strong or moderate CYP3A inhibitors
                              • Rucaparib and olaparib can interfere with renal transport creatinine proteins; niraparib does not have that same impact, so elevation in creatinine should not be seen

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                            • PARP Inhibitor Toxicity: Bone Marrow Suppression[16,15,14,36]

                              • It is very important to allow your patients to have time to recover from their toxicities before you try to start them on PARP inhibitor maintenance
                              • This may help to lessen and mitigate some of the potential toxicities

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                            • Niraparib Dose Level by Month on Treatment[2,37,33]

                              • Many patients did require dose-modifications on the NOVA trial related to toxicities
                              • The most common dose after patients had been on treatment for a prolonged period was 200 mg

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                              Slide 55.

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                            • NOVA: Integrated Analysis to Predict Which Patients Are at Risk for Grade 3/4 Thrombocytopenia[2,37,33]

                              • Investigators sought variables which were predictive of experiencing significant levels of thrombocytopenia
                              • Two identified as important were weight and baseline platelet count
                              • Patients who have those parameters might be considered for starting at a lower dose (eg, 200 mg/day)

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                              Slide 56.

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                            • Dose Modifications Result in Decreased Incidence of AEs[2,33]

                              • Patients who had required dose reductions were able to continue on the trial and were able to tolerate the medications

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                            • Estimated Probability of PFS by Dose Level After Month 3[33]

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                              • PARP Inhibitor Toxicity: Fatigue

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                                • PARP Inhibitory Toxicity: Elevated LFTs[4,16]

                                  • In general, there was a short, limited increase in LFTs which did improve over time
                                  • This did not require dose modification or dose delay, and was not associated with liver dysfunction

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                                • PARP Inhibitors: Practical Implications

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                                  • Patients as Self-Advocates[41]

                                    • Patients are becoming their own advocates, and they are often helped on this by a toolkit developed by the National Coalition of Cancer Survivorship (NCCS), the oldest cancer survival advocacy organization in the United States
                                    • The toolkit teaches patients the skills they need to be more proactive in our own medical care

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                                  • SHARE Cancer Support: www.sharecancersupport.org[42]

                                    • The smoothest journeys of all ovarian cancer patients are the ones that include peer-support
                                    • Every ovarian cancer survivor can have unparalleled peer-support from the SHARE organization which serves both breast cancer and ovarian cancer survivors
                                    • SHARE is a free, non-profit nation-wide support organization which operates a phone hotline for ovarian cancer patients staffed by ovarian cancer survivors

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                                  • Effective Communication

                                    • It is imperative that patients know the clearest communication pathway from the doctor to the patient (ie, portal, secure email, phone call)
                                    • In the era of the 5-minute doctor visit, it is helpful to the patient if there is a team approach at the doctor's office, starting with the receptionist, and including office staff, nurses, and others who will spend more time with her than the doctor will be able to

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                                  • To Be Continued

                                    • Women may need "dialogue reframing" to help see themselves as someone other than an ovarian cancer victim, but rather, a survivor
                                    • A 5-minute conversation about ovarian cancer as a chronic disease can completely change a patent's attitude
                                    • The fact that a highly-trained professional explains what it means to have a chronic disease is very meaningful and empowering to the patient

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                                  • This content has been condensed for improved clarity.

                                  •  

                                  Educational Impact Challenge

                                  What did you learn from this activity? Please click on the "Next" button to proceed to a brief survey to see how your knowledge improved after the education. You can also see how your answers compare with those of your peers.

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