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Physicians' Education Resource®, LLC 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 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physicians' Education Resource®, LLC, is approved by the California Board of Registered Nursing, Provider #16669, for 1.0 Contact Hour.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Tesaro, Inc.

Oncology Best Practice™: Expert Perspectives to Incorporate Evidence on PARP Inhibitors into Practice and Optimize the Medical Management of Ovarian Cancer

Release Date: October 31, 2017
Expiration Date: October 31, 2018
Media: Internet - based

 

Activity Overview

New clinical treatment options for patients with ovarian cancer continue to emerge at a rapid pace, including several options that target the poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) family of enzymes. FDA approval has been granted for several of these agents, altering the treatment landscape. In order to optimize clinical decision-making regarding medical therapies for ovarian cancer, it is imperative for clinicians to be aware of the latest data pertaining to PARP inhibition. This activity is designed to enhance knowledge of the mechanistic rationale for the application of PARP inhibitors in the treatment of patients with ovarian cancer, as well as strategies to personalize care for these patients and mitigate adverse events associated with this treatment modality. The perspectives of leading clinical experts in the management of ovarian cancer will be provided throughout this activity.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Tesaro, Inc.

CME/CE Activity Table of Contents

  • Translating Tumor Characteristics to PARP Inhibitor Development in Ovarian Cancer
  • Assessing Methods to Optimize Personalized Care in Ovarian Cancer
  • Current Strategies to Optimize PARP Inhibition in Multiple Lines of Care
  • Management of Treatment-Related Toxicities With PARP Inhibitor Use

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 activity is directed toward medical, surgical and radiation oncologists who treat or manage patients with ovarian cancer. Fellows, nurses, nurse practitioners, physician assistants, researchers, pharmacists and other healthcare professionals interested in the treatment or management of these tumors are also invited to participate.

Learning Objectives

At the conclusion of this activity, you should be better prepared to:

  • Describe how PARP inhibition strategies have been applied to the management of recurrent ovarian cancer
  • Discuss how care can be personalized via the use of testing strategies in BRCA-mutant and non—BRCA-mutant patient populations with ovarian cancer
  • Examine the current emerging roles of PARP inhibitors (PARPis) in maintenance therapy for ovarian cancer
  • Describe effective strategies to proactively plan for and manage treatment-related toxicities in the setting of ovarian cancer

Faculty, Staff, and Planners' Disclosures

Faculty

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

Disclosure: Grant/Research Support – Roche Laboratories.

Susan Campos, MD
Assistant Professor of Medicine
Harvard Medical School
Dana Farber Cancer Institute
Boston, MA
 

Disclosure: Consultant – Advisory Board, Clovis.

Maurie Markman, MD
President, Medicine & Science
Cancer Treatment Centers of America
Clinical Professor of Medicine
Drexel University College of Medicine
Philadelphia, PA

Disclosure: Celgene; Speaker’s Bureau – Genentech, AstraZeneca, Clovis, Tesaro, Inc.

The staff of PER® 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®.

PER Pulse™ Recap

PER Pulse™ Recap (1 of 3)

Oncology Best Practice™: Expert Perspectives to Incorporate Evidence on PARP Inhibitors Into Practice and Optimize the Medical Management of Ovarian Cancer

Translating Tumor Characteristics to PARP Inhibitor Development in Ovarian Cancer

Ovarian cancer remains the leading cause of gynecologic cancer mortality. In 2017, an estimated 22,440 new cases of ovarian cancer will be diagnosed in the United States, with more than 14,000 deaths.1 Recent advancements in the understanding of the molecular biology of ovarian cancer have led to the emergence of targeted therapies, such as poly-ADP ribose polymerase (PARP) inhibitors, that can disrupt DNA repair. Damage to DNA can involve single- or double-stranded breaks. Multiple repair pathways are currently known to preserve DNA integrity and maintain cell survival.2 The role of PARP inhibitors in the repair of DNA has become progressively well understood, and there are several models that are available to account for how PARP inhibition may lead to tumor cell death. If PARP enzyme activity is inhibited, then unrepaired single-strand breaks may become double-strand breaks during the replication process. Normally, this damage would be repaired through homologous recombination mechanisms, which are dependent on functional BRCA genes. However, for cancer cells that have homologous repair deficiency (HRD), including those with BRCA mutations,2 there are no effective repair pathways left, resulting in cell death. Some recent studies challenge this concept.

The mechanism for some PARP inhibitors is related not only to the catalytic inhibition of PARP1/2, but also “trapping” of PARP–DNA complexes.3,4 PARP trapping may be more cytotoxic than the limitation of its catalytic activity. This trapping mechanism accounts for synergism with certain chemotherapy agents. PARP trapping does not occur to the same degree with all PARP inhibitors. Other cellular mechanisms have also been put forward to account for the efficacy of PARP inhibition in the treatment of cancers. One such concept involves defective BRCA1 recruitment to damaged DNA,5 while another involves the role of PARP inhibitors in mediating nonhomologous end joining.

In this activity, Michael Birrer, MD, PhD, Susana Campos, MD, MPH, and Maurie Markman, MD discuss several key topics pertaining to the use of PARP inhibitor therapy for patients with ovarian cancer. For more information, please go to www.gotoper.com.

References:

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi: 10.3322/caac.21387.
  2. Evans T, Matulonis U. PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther Adv Med Oncol. 2017;9(4):253-267. doi: 10.1177/1758834016687254.
  3. Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016;115(10):1157-1173. doi: 10.1038/bjc.2016.311.
  4. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012:72(21):5588-5599. doi: 10.1158/0008-5472.CAN-12-2753.
  5. Li M, Yu X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell. 2013;23(5):693-704. doi: 10.1016/j.ccr.2013.03.025.



PER Pulse™ Recap (2 of 3)

Optimizing Care for Patients With Ovarian Cancer

Awareness of the germline and somatic mutational status of patients with ovarian cancer has helped to shape management approaches for these patients. Recent advancements in testing technology, including next-generation sequencing, have facilitated the exploration of genomic and molecular changes in epithelial ovarian cancer that may help to pair individual patients with appropriately targeted therapy.1 BRCA1 and BRCA2 are ovarian cancer susceptibility genes. Approximately 11% to 15% of patients with epithelial ovarian cancer have germline BRCA1/2 mutations.2 Nearly 1 in 4 ovarian cancers is associated with germline mutations, and close to 30% of these have non-BRCA1/2 mutations.2 Although most tumors that have homologous repair deficiencies (HRDs) are found in patients who have germline BRCA1 and BRCA2 mutations, there are other homologous repair pathway genes that carry aberrations. Clinical study results have shown that poly-ADP ribose polymerase (PARP) inhibitors may have efficacy beyond patients with germline BRCA mutations, through assessment of HRD status.1 Both germline and somatic mutations in HRD genes have been associated with ovarian cancer. Given the recent approvals of PARP inhibitors in the maintenance setting for patients with ovarian cancer, the use of HRD testing may help clinicians to guide discussion of the risks and benefits for patients who may be candidates for this therapeutic modality.

PARP inhibitors have become an important addition to the treatment armamentarium for patients with ovarian cancer, showing significant improvements in key clinical outcomes. In this educational activity, Drs Campos, Markman, and Birrer discuss the implications of key studies of PARP inhibition in the treatment of ovarian cancer and diagnostic testing that may help to optimize their potential application.3-7 For more information, please go to www.gotoper.com.

References

  1. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4. doi: 10.1186/s40661-017-0039-8.
  2. Wang ZC, Birkbak NK, Culhane AC, et al; Australian Ovarian Cancer Study Group. Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome. Clin Cancer Res. 2012;18(20):5806-5815. doi: 10.1158/1078-0432.CCR-12-0857.
  3. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. doi: 10.1056/NEJMoa1105535.
  4. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. doi: 10.1016/S1470-2045(14)70228-1.
  5. Pujade-Lauraine E, Ledermann JA, Selle F, et al; 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. Lancet Oncol. 2017;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2.
  6. Mirza M, Monk B, Herrstedt J, et al; 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.
  7. Coleman RL, Oza AM, Lorusso D, et al; 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 online September 12, 2017]. Lancet. doi: 10.1016/S0140-6736(17)32440-6.



PER Pulse™ Recap (3 of 3)

Management of Treatment-Related Toxicities With PARP Inhibitor Use

Clinicians need to be aware of adverse events (AEs) commonly associated with the use of poly-ADP ribose polymerase (PARP) inhibition in the management of patients with ovarian cancer. This is particularly true as the potential for longer courses of therapy is being realized with new indications in the maintenance setting and potential applications in the frontline management of ovarian cancer. PARP inhibitors are generally well tolerated, although there are both class-wide and treatment-specific AEs that clinicians should be cognizant of. Many adverse reactions are often resolved with appropriate management strategies.

Commonly reported AEs with the use of olaparib include anemia, fatigue, nausea, and vomiting.1 These events are usually of a low-grade intensity. A more serious AE noted in clinical investigation was the emergence of myelodysplastic syndrome (MDS) and its transformation to acute myeloid leukemia (AML) in patients treated with olaparib, although the incidence was quite low (<1%).2 Pneumonitis has also occurred in patients who have been treated with olaparib; treatment with olaparib should be interrupted if a diagnosis of pneumonitis is suspected and discontinued if pneumonitis is confirmed.3

In the NOVA trial, the most common treatment-emergent grade 3/4 AEs for patients treated with niraparib were anemia, neutropenia, and thrombocytopenia.4 These AE tended to occur early in the course of treatment and resolved with dose modification. The rates of MDS/AML were 1.4% in patients receiving niraparib versus 1.1% of patients receiving placebo.4 As with olaparib, the overall incidence of MDS/AML in patients receiving niraparib across clinical studies was less than 1%.5 There should be regular monitoring for hematologic toxicity, and niraparib should be discontinued if MDS/AML is confirmed.5 Clinicians should also be vigilant for problems associated with hypertension and hypertensive crisis from the use of niraparib; in the NOVA study, grade 3/4 hypertension occurred in 9% of patients compared with 2% receiving placebo.4 Blood pressure and heart monitoring should take place regularly, according to prescribing information, with incorporation of antihypertensive therapy and niraparib dose modification if needed.5

With rucaparib, commonly reported treatment-related adverse events were nausea, fatigue, vomiting, anemia, and treatment-related elevations in aspartate transaminase/alanine transaminase.6 Again, approximately 1% of patients treated with oral rucaparib have been diagnosed with MDS/AML.7 Patients should be assessed for hematologic toxicity at baseline and on a monthly basis after treatment initiation. If MDS/AML is confirmed, then treatment with rucaparib should be discontinued.7

For more information and faculty discussion on this topic, please go to www.gotoper.com.

References

  1. 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(9):852-861. doi: 10.1016/S1470-2045(11)70214-5.
  2. Ricks TK, Chiu H-J, Ison G, et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol. 2015;5:222. doi: 10.3389/fonc.2015.00222.
  3. Lynparza [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. https://www.azpicentral.com/lynparza_tb/pi_lynparza_tb.pdf#page=1. Accessed November 28, 2017.
  4. Mirza MR, Monk BJ, Herrstedt J, et al; 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. Zejula [prescribing information]. Waltham, MA: TESARO, Inc.; 2017. Zejula.com/application/files/4115/0422/0987/Zejula_niraparib_Full_Prescribing_Information.pdf.  Accessed November 28, 2017.
  6. O’Sullivan Coyne G, Chen AP, Meehan R, Doroshow JH. PARP inhibitors in reproductive system cancers: current use and developments. Drugs. 2017;77(2):113-130. doi: 10.1007/s40265-016-0688-7.
  7. Rubraca [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2017. Clovisoncology.com/files/rubraca-prescribing-info.pdf. Accessed November 28, 2017.






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