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Physicians' Education Resource®, LLC (PER®)is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgement of Commercial Support

This activity is supported by educational grants from AstraZeneca, Clovis Oncology, Myriad Genetics, and Tesaro.

Community Practice Connections™: Show Me the Data™: Leveraging Evidence to Optimize Applications of PARP Inhibitor Strategies in Ovarian Cancer


Release Date: June 29, 2018
Expiration Date: June 29, 2019
Media: Internet - based
 

Activity Overview

Recent poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor approvals and expanded indications for these treatments have heralded an advancement in the application of personalized medicine for your patients with ovarian cancer. Given the rapid accumulation of data and the dynamic nature of clinical practice, it is important for you to have the tools to effectively apply new information in a variety of clinical settings and scenarios to help optimize patient outcomes. We have developed an educational activity to provide you with those tools. This activity will help to solidify your awareness of key studies exploring the use of PARP inhibition in maintenance and therapeutic settings, as well as provide you with insights into testing strategies that are being evaluated to help personalize treatment approaches to ovarian cancer, as well as maintenance treatment sequencing considerations.

Acknowledgment of Commercial Support

This activity is supported by educational grants from AstraZeneca, Clovis Oncology, Myriad Genetics, and Tesaro.

Instructions for This Activity and Receiving Credit

  • You will need to login to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review videos/content until you finish the presentation.
  • At the end of the activity, “educational content/video files” will be available for your reference.
  • In order to receive a CME/CE certificate, participants must complete the activity.
  • Complete the posttest and pass with a score of 70% or higher, complete the evaluation and then click on request for credit. Participants may immediately download a CME/CE certificate upon completion of these steps.


Target Audience

This educational activity is intended for clinicians who have an interest in the treatment of patients with ovarian cancer, including oncologists, obstetricians/gynecologists, nurses, physician assistants, fellows, and residents.

Learning Objectives

Upon completion of this activity, you should be able to:

  1. Report clinical study designs, as well as efficacy and toxicity findings, from trials that have evaluated PARP inhibitors among patients with ovarian cancer
  2. Assess the role of germline and somatic mutation assessment to guide decision making concerning PARP inhibition strategies in ovarian cancer settings
  3. Describe the evolving use of homologous recombination deficiency testing in BRCA-mutant and non–BRCA-mutant patient populations with ovarian cancer
  4. Apply evidence concerning the use of maintenance strategies to clinical settings in which patients with ovarian cancer are managed

Faculty, Staff, and Planners' Disclosures

Michael J. Birrer, MD, PhD
Director, UAB Comprehensive Cancer Center
Professor of Medicine, Division of Hematology & Oncology
Birmingham, AL

 

Disclosure: No relevant financial relationships with commercial interests to disclose.
 

Robert L. Coleman, MD, FACOG, FACS
Professor and Executive Director, Cancer Network Research
Ann Rife Cox Chair in Gynecology
Department of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas

Disclosures: Grant Research Support: Array BioPharma, AstraZeneca, Clovis Oncology, EMD Serono, Gradalis, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck; Consultant: AbbVie, Debiopharm, Genmab, ImmunoGen, Merrimack Pharmaceuticals, Navigant Consulting, Perthera, Tesaro, Vaniam Group, Verastem; Other: Advisory Board: AstraZeneca, Bayer Healthcare, Inc, Caris Life Sciences, Cerulean Pharma, Clovis Oncology, GamaMabs Pharma, Janssen Pharmaceutical Companies of Johnson & Johnson, Novocure, Precision Oncology, Roche, Tesaro.

Ursula A. Matulonis, MD
Director, Gynecologic Oncology
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
 

Disclosure: Grant Research Support: Merck, Novartis; Consultant: Merck, Geneos, Myriad Genetics, 2X Oncology, Fujifilm.

Bradley J. Monk, MD, FACS, FACOG
Professor, Gynecologic Oncology
Arizona Oncology (US Oncology Network)
University of Arizona and Creighton University
Phoenix, Arizona
 

Disclosure: AbbVie, Advaxis, Amgen, AstraZeneca, Biodesix, Clovis Oncology, Genmab, Gradalis, ImmunoGen, Incyte, Insys Therapeutics, Mateon Therapeutics, Merck, Myriad Genetics, Perthera, Pfizer, Precision Oncology, Roche/Genentech, Tesaro, VBL; Speakers Bureau:  AstraZeneca, Clovis Oncology, Janssen/Johnson & Johnson, Roche/ Genentech, Tesaro.

The staff of Physicians' Education Resource®, LLC, and Michael J. Birrer, MD, PhD, have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/CE activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME/CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER or any of the companies that provided commercial support for this activity.

PER Pulse Recap™

1 of 3
PER Pulse™ Recap

When Are PARP Inhibitors Best Used in the Treatment Paradigm?

Recent advances in targeted therapies such as bevacizumab and poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors for patients with ovarian cancer offer the potential to improve outcomes for patients in different settings, including extension of the disease-free treatment interval after induction and improvement of treatment response after first-line therapy. However, these advances also increase the complexity of treatment sequencing for patients with ovarian cancer.1

With respect to PARP inhibitors, recent studies have looked at treatment of patients with advanced ovarian cancer after disease progression on multiple lines of platinum-containing chemotherapy, as well as in the maintenance setting. Although the initial treatment approvals for PARP inhibitors focused on patients who had BRCA1/2 mutations, maintenance indications thus far have included all patients with platinum-sensitivity, regardless of BRCA mutational status. The understanding of the efficacy of PARP inhibitors in patients with homologous recombination repair deficiency has been built largely upon the concept of synthetic lethality. For normal cells that do not have a deficiency in homologous recombination repair, homologous recombination can be used to repair DNA and allow cell survival. In cells with homologous recombination repair deficiency, this effective technique is unavailable, leading to cell death. According to 1 analysis, more than 50% of epithelial ovarian cancers may have deficiencies in homologous recombination repair.2

For patients with platinum-sensitive recurrent ovarian cancer, several PARP inhibitors are available for consideration for maintenance therapy, particularly in those patients for whom bevacizumab is not tolerated or indicated. The SOLO-2 study and Study 19 established the efficacy of olaparib maintenance therapy for patients with platinum-sensitive, relapsed ovarian cancer with a germline BRCA mutation. In the SOLO-2 study, patients who were treated with olaparib had an investigator-assessed median progression-free survival of 19.1 months, compared with 5.5 months for patients who were treated with placebo.3 Niraparib demonstrated efficacy as maintenance therapy for platinum-sensitive, relapsed ovarian cancer, regardless of BRCA mutational or homologous recombination deficiency (HRD) status in the NOVA trial.4 Rucaparib has also recently been approved as maintenance therapy for platinum-sensitive, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, based on the results of the ARIEL3 trial.5

A variety of clinical combinations with targeted therapies are also being studied. The PAOLA-1 study is assessing the addition of olaparib to first-line treatment combining platinum-taxane chemotherapy and bevacizumab concurrent with chemotherapy and in maintenance.6 The IMaGYN050 study is investigating the combination of atezolizumab plus paclitaxel plus carboplatin plus bevacizumab for patients with stage III or IV ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with residual disease following tumor reductive surgery.7 Many combinations of PARP inhibitors and checkpoint inhibitors are underway. Even triplet targeted therapy involving the combination of bevacizumab, PARP inhibitors, and checkpoint inhibition is being assessed for patients with ovarian cancer.

References:

  1. Herzog TJ, Monk BJ. Bringing new medicines to women with epithelial ovarian cancer: what is the unmet clinical need? Gynecol Oncol Res Pract. 2017;4:13. doi: 10.1186/s40661-017-0050-0.
  2. Konstantinopoulos PA, Ceccaldi R, Shpairo GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154. doi: 10.1158/2159-8290.CD-15-071.
  3. Pujade-Lauraine E, Ledermann JA, Selle F, et al; and the SOLO2/ENGOT-Ov21 Investigators. 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 [published correction appears in Lancet Oncol. 2017;18(9):e510. doi: 10.1016/S1470-2045(17)30639-3]. Lancet Oncol. 2017;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2.
  4. Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310.
  5. Coleman RL, Oza AM, Lorusso D, et al; and the ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2017;390(10106):1948. doi: 10.1016/S0140-6736(17)32702-2]. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.
  6. Platine, Avastin and OLAparib in 1st Line (PAOLA-1).  clinicaltrials.gov/ct2/show/NCT02477644. Updated September 14, 2016. Accessed April 17, 2018.
  7. A Study of Atezolizumab Versus Placebo in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Participants With Newly-Diagnosed Stage III or Stage IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (IMagyn050). clinicaltrials.gov/ct2/show/NCT03038100. Updated April 10, 2018. Accessed April 17, 2018.

2 of 3
PER Pulse™ Recap

Which Molecular Markers Have the Potential to Influence Treatment Decisions With PARP Inhibitors?

The ability to identify genes associated with ovarian cancer may allow clinicians to offer predictive testing in families who may be susceptible to the emergence of ovarian cancer. In one study, 6% of patients had germline loss of function mutations in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53.1 Next-generation sequencing may allow for broader testing at lower cost.2,3

Defective homologous recombination repair leads to the creation of uniparental deletions and loss of heterozygosity. One study focusing on  loss of heterozygosity (LOH)-based clustering of tumors led to the designation of 2 cohorts: patients who were LOH “high” (extensive LOH) and those were LOH “low” (considerably less LOH). This study found that patients in different cohorts differed with respect to chemotherapy resistance, and the existence of a correlation between degree of LOH and progression-free survival (PFS).4

There are different ways to define HR deficiency. Different HR deficiency assays are being developed to help assess for the “BRCAness” phenotype.5 One such assay has been designed to assess the extent of LOH, telomeric allelic imbalance, and larger-scale state transitions in DNA.6

Part 1 of the ARIEL2 study was designed to assess the ability of tumor genomic LOH to predict the response to poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor therapy. In this study, patients who had recurrent, platinum-sensitive, high-grade ovarian cancer were classified into 1 of 3 subgroups: BRCA mutant, BRCA wild-type and LOH high, or BRCA wild-type and LOH low. Median PFS for patients who received rucaparib was 12.8 months (95% CI, 9.0-14.7 months) among evaluable BRCA-mutant patients, 5.7 months (95% CI, 5.3-7.6 months) in the BRCA wild-type and LOH high group, and 5.2 months (95% CI, 3.6-5.5 months) in the BRCA wild-type and LOH low group.7 Patients who had either a germline BRCA (gBRCA) mutation or BRCA wild-type and high LOH had significantly greater response to rucaparib than patients with BRCA wild type and low LOH. The presence of somatic BRCA mutations is a viable target, and patients with germline and somatic mutations had similar response rates in ARIEL2.7

The ARIEL3 study assessed the role of rucaparib in the maintenance treatment of patients with platinum-sensitive, recurrent, high-grade ovarian, fallopian tube, or primary peritoneal cancer. In this study, patients with BRCA wild-type, LOH-high ovarian cancer who were treated with rucaparib had an investigator-reviewed median PFS of 9.7 months, compared with 5.4 months in patients treated with placebo (hazard ratio [HR], 0.44; P <.0001).8 Patients with BRCA wild-type, LOH-low ovarian cancer who were treated with rucaparib had an investigator-assessed median PFS of 6.7 months, compared with 5.4 months for patients treated with placebo (HR, 0.58; P =.0049).8

In the NOVA study, patients who were gBRCA mutant and were treated with niraparib had a median PFS of 21.0 months, compared with 5.5 months for gBRCA-mutant patients who were treated with placebo (HR, 0.27; P <.0001).9 Among patients who were BRCA wild-type and classified as homologous recombination deficiency (HRD)-positive, median PFS was 12.9 months, compared with 3.8 months in patients treated with placebo (HR, 0.38; P <.0001). Among patients who were HRD-negative, median PFS was 6.9 months, compared with 3.8 months in patients treated with placebo (HR, 0.58; P=.02).9

References:

  1. Konstantinopoulos PA, Ceccaldi R, Shpairo GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154. doi: 10.1158/2159-8290.CD-15-0714.
  2. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032-18037. doi: 10.1073/pnas.1115052108.
  3. Hall MJ, Obeid EI, Schwartz SC, Schwartz SC, Mantia-Smaldone G, Forman AD, Daly MB. Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond. Gynecol Oncol. 2016;140(3):565-574. doi: 10.1016/j.ygyno.2016.01.019.
  4. Wang ZC, Birkbak NJ, Culhane AC, et al; for the Australian Ovarian Cancer Study Group and Matulonis UA. Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcomes. Clin Cancer Res. 2012;18(20):5806-5815. doi: 10.1158/1078-0432.CCR-12-0857.
  5. Kristeleit RS, Miller RE, Kohn EC. Gynecologic cancers: emerging novel strategies for targeting DNA repair deficiency. Am Soc Clin Oncol Educ Book. 2016;35:e259-e268. doi: 10.14694/EDBK_159086.
  6. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2(4):482-490. doi: 10.1001/jamaoncol.2015.5495.
  7. 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(1):75-87.  doi: 10.1016/S1470-2045(16)30559-9.
  8. Ledermann J, Oza AM, Lorusso D, et al. ARIEL 3: A phase 3, randomised, double-blind study of rucaparib versus placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LAB40_PR. academic.oup.com/annonc/article/28/suppl_5/mdx440.034/4109946
  9. Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1016/S1470-2045(16)30559-9.

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PER Pulse™ Recap

How Can PARP Inhibitor Characteristics Inform Treatment Choices?

There are a variety of factors that may influence treatment decisions regarding the use of poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors. With respect to treatment options, olaparib is approved for patients who have (or are suspected to have) deleterious germline BRCA-mutated advanced ovarian cancer who have received 3 or more lines of chemotherapy. This approval was largely based upon a single-arm study of patients with advanced ovarian cancer and germline BRCA1/2 mutations.1 The overall response rate (ORR) was 31.1%; for the patients who had baseline measurable disease and were treated with 3 or more lines of chemotherapy, the ORR was 34%, with a median duration of response (DOR) of 7.9 months. Of note, patients with platinum-sensitive cancer had an ORR of 46%. Rucaparib is currently approved as treatment for patients who have germline and/or somatic BRCA-mutated advanced ovarian cancer who have been treated with 2 or more lines of chemotherapy. An integrated analysis of data from Study 10 and the ARIEL2 study showed an ORR of 53.8%, with a median DOR of 9.2 months.2

With respect to maintenance options, olaparib is currently approved as maintenance therapy for patients who have recurrent ovarian cancer who are in complete response (CR) or partial response (PR) to platinum-based chemotherapy.3 Niraparib is approved as maintenance therapy for patients with recurrent ovarian cancer who have had PR or CR to platinum-based chemotherapy.4 Rucaparib has also recently been approved as maintenance therapy for patients with recurrent ovarian cancer who are in CR or PR to platinum-based chemotherapy.5

Adverse events (AEs) associated with PARP inhibitor use are generally mild to moderate in nature. Common AEs include anemia, fatigue, nausea, and vomiting. These frequently occur during the early stage of treatment, are often transient, and may not require discontinuation of PARP inhibitor therapy.

Differences exist among PARP inhibitors with respect to drug-drug interactions and differences in metabolism. Price may also be an important factor for clinicians to consider when selecting therapy for their patients with ovarian cancer. Special clinical situations may also arise that can help to inform treatment selection. In the instance of situations where ovarian cancer may have metastasized to the central nervous system (CNS), it is important to remember that although olaparib, niraparib, and veliparib all cross the blood-brain barrier,6-8 rucaparib has limited penetration.

  • PARP inhibitor characteristics can help to inform treatment choices for patients with ovarian cancer.
  • Given the comparable efficacy of the 3 PARP inhibitors that are currently available for the treatment of these patients, other characteristics may play a more prominent role in guiding treatment selection, including individual drug toxicities, drug-drug interactions, schedule, and price.
  • Furthermore, special clinical situations such as the treatment of CNS disease may also help to inform treatment selection.

References

  1. Kaufman B, Shapira-Frommer R, Schumtzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250. doi: 10.1200/JCO.2014.56.2728
  2. Oza AM, Tinker AV, Oaknin A, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147(2):267-275. https://doi.org/10.1016/j.ygyno.2017.08.022.3.
  3. Lynparza [prescribing information]. Wilmington, DE: AstraZeneca; 2014. https://www.azpicentral.com/lynparza_tb/pi_lynparza_tb.pdf#page=1. Revised January 2018. Accessed April 17, 2018.
  4. Zejula [prescribing information]. Waltham, MA: Tesaro; 2017. https://www.zejula.com/application/files/1715/2156/1557/prescribing_information.pdf. Revised August 2017. Accessed April 17, 2018.
  5. Rubraca [prescribing information]. Boulder, CO: Clovis Oncology; 2016. http://clovisoncology.com/files/rubraca-prescribing-info.pdf. Revised April 2018. Accessed April 17, 2018.
  6. Chalmers A, Cruickshank G, Dunn L, et al. Results of the OPARATIC trial: a phase I dose escalation study of olaparib in combination with temozolomide in patients with relapsed glioblastoma. Presented at: 2017 NCRI Cancer Conference; November 5-8, 2017; Liverpool, UK.  http://abstracts.ncri.org.uk/abstract/results-of-the-oparatic-trial-a-phase-i-dose-escalation-study-of-olaparib-in-combination-with-temozolomide-tmz-in-patients-with-relapsed-glioblastoma-gbm/.
  7. Mikule K, Wilcoxen K. The PARP inhibitor, niraparib, crosses the blood brain barrier in rodents and is efficacious in a BRCA2-mutant intracranial tumor model. Mol Cancer Ther. 2015;14(12 suppl 2): Abstract nr B168. doi: 10.1158/1535-7163.TARG-15-B168. http://mct.aacrjournals.org/content/14/12_Supplement_2/B168.
  8. Meehan RS, Chen AP. New treatment option for ovarian cancer: PARP inhibitors. Gynecol Oncol Res Pract. 2016;3:3. doi: 10.1186/s40661-016-0024-7.






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