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Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education 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.

Physicians' Education Resource®, LLC, is approved by the California Board of Registered Nursing, Provider #16669, for 1.5 Contact Hours.

Acknowledgement of Commercial Support

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

Community Practice Connections™: Evolving Applications for PARP Inhibitors in Ovarian Cancer: Building on a Solid Foundation


Release Date: August 15, 2018
Expiration Date: August 15, 2019
Media: Internet - based

Activity Overview

The landscape of therapeutic options for patients with ovarian cancer continues to evolve at a rapid pace, including the approval of multiple PARP inhibitors for treatment and maintenance indications following the results of recent key studies. It can be difficult for any clinician to keep up with the accelerated pace and volume of clinical advancements associated with PARP inhibition, and we have created an educational activity to help you to stay current and arm yourselves with the clinical knowledge and insight necessary to optimize safety and efficacy outcomes for your patients.

This web-based activity, based upon content presented at an ancillary event to the 2018 ASCO Annual Meeting, will present the latest data on PARP inhibition and the clinical implications of the data for your practice. The format will feature video clips of leading clinical experts in the treatment of ovarian cancer, who will address key learning points pertaining to the use of PARP inhibition in ovarian cancer. Multiple topics will be explored, including strategies for optimizing application of PARP inhibitor therapy for your patients when appropriate, approaches to assist you with the mitigation of PARP inhibitor-associated adverse events, and considerations for potential future directions and applications for PARP inhibition.

Acknowledgement of Commercial Support

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

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 program is intended for medical oncologists, surgical oncologists, and radiation oncologists interested in the treatment of ovarian cancer. Nurse practitioners, physician assistants, nurses, and other healthcare professionals involved in the management of patients with ovarian cancer are also invited to participate.

Learning Objectives

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

  • Define safety and efficacy outcomes from clinical trials of PARP inhibitors, both in the maintenance setting and in the setting of recurrence following prior use of platinum-based therapy
  • Identify strategies for anticipating, recognizing, and managing adverse events of PARP inhibitor therapy in patients with ovarian cancer
  • Describe the therapeutic rationale for use of PARP inhibitors in combination with other novel treatments, including evaluating specific clinical trials using PARP inhibitors in combination and recognizing the potential for enrolling patients in these trials
  • Utilize the most up-to-date clinical evidence on PARP inhibitors for clinical decision making in patients with ovarian cancer in the context of current evolving treatment options

Faculty, Staff, and Planners' Disclosures

Faculty

Michael J. Birrer, MD, PhD
Director
Comprehensive Cancer Center
Professor of Medicine, Ob/Gyn, and Pathology
University of Alabama at Birmingham
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, TX

Disclosure: Grant/Research Support: AstraZeneca, Clovis Oncology, Genentech-Roche, Janssen, Merck; Consultant: AbbVie, Cell Medica, DelMar Pharmaceuticals, Geistlich, Genmab, ImmunoGen, Perthera, Takeda, Tesaro; Speakers Bureau: Clovis Oncology, Roche; Other: Scientific/Advisory Board: Aravive Biologics, AstraZeneca, Bayer Healthcare, Caris Life Sciences, Clovis Oncology, Eisai-Morphotek, GamaMabs, Genmab, ImmunoGen, Janssen, Myriad Genetics, Precision Oncology, Regeneron Pharmaceuticals.

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

Disclosure: Consultant: Advaxis, Aravive, Geistlich, Genmab, ImmunoGen, Mateon (formerly Oxigene), Merck, Myriad Genetics, Perthera, Pfizer, Takeda, VBL; Speakers Bureau: AstraZeneca, Clovis Oncology, Janssen/Johnson & Johnson, Roche-Genentech, Tesaro.

David O’Malley, MD
Professor
Director, Gyn Oncology Clinical Research
Co-Director, Gyn Oncology Phase I Program
James Cancer Center - Ohio State University
Columbus, OH

Disclosure: Grant/Research Support: Amgen, Array, AstraZeneca, BMS, Cerulean, Clovis Oncology, EMD Serono, Ergomed, Genentech-Roche, ImmunoGen, Janssen, PharmaMar, Regeneron, Stemcentrx, VentiRx; Consultant: Clovis Oncology, AstraZeneca, Tesaro, AbbVie, Janssen, Ambrx, Myriad Genetics.

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™

1 of 3
PER Pulse™ Recap

STAYING ON THE LEADING EDGE OF PARP INHIBITOR THERAPY IN TODAY’S CLINICAL PRACTICE

Both treatment and maintenance therapy paradigms for patients with ovarian cancer have been influenced by the emergence of poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors over the past few years. Olaparib was initially approved by the Food and Drug Administration (FDA) in 2014 for the treatment of patients with germline BRCA-mutated (gBRCAm) ovarian cancer who had received ≥3 lines of chemotherapy, along with a companion diagnostic test.1 This approval was largely based upon the efficacy results of a single-arm phase II study, as well as safety results from several other studies.1,2 This approval was followed in 2016 by the FDA’s approval of rucaparib as monotherapy treatment for patients with either gBRCAm or somatic BRCA-mutated ovarian cancer who had received ≥2 lines of chemotherapy, largely upon the results of 2 multicenter, single-arm, open label clinical trials (ARIEL2 and Study 10).3,4

With respect to maintenance therapy for patients with ovarian cancer, 3 PARP inhibitors have received FDA approval. Niraparib was approved for maintenance therapy in patients with platinum-sensitive ovarian cancer in 2017. The NOVA study evaluated niraparib versus placebo for patients with gBRCAm ovarian cancer and those without gBRCAm cancer.5 Patients with gBRCAm ovarian cancer who were treated with niraparib had a median progression-free survival (PFS) of 21.0 months compared with 5.5 months for those treated with placebo (HR, 0.27; P <.001). For patients who did not have gBRCAm cancer but were regarded as homologous recombination deficiency (HRD) positive, the median PFS was 12.9 months for those who received niraparib and 3.8 months for those who received placebo.5

Olaparib was approved for maintenance therapy of patients with recurrent ovarian cancer who have achieved complete or partial response to platinum-based chemotherapy, following 2 randomized, placebo-controlled studies. The SOLO-2 study randomized patients with BRCA-mutated ovarian cancer 2:1 to receive olaparib tablets (300 mg twice daily) or placebo until disease progression or intolerable treatment toxicity.6 Patients in the olaparib arm had a median PFS of 19.1 months compared with 5.5 months in patients receiving placebo (HR, 0.30; P <.0001).6 The maintenance indication was also supported by data from Study 19, in which patients were noted to have a significant improvement in PFS with olaparib, with a median PFS of 8.4 months compared with 4.8 months among patients receiving placebo (HR, 0.35; P <.0001).7

Rucaparib was recently approved for the indication of maintenance therapy following the ARIEL3 study, in which patients with platinum-sensitive, high-grade serous or endometrioid ovarian cancer were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo.8 Patients had to have shown a response to penultimate platinum therapy and were assessed every 12 weeks, with a primary endpoint of investigator-assessed PFS. Patients with BRCA-mutated ovarian carcinoma who were treated with rucaparib had a median PFS of 16.6 months compared with 5.4 months for those receiving placebo (HR, 0.23; P <.0001). For patients who were HRD positive, the median PFS was 13.6 months with rucaparib versus 5.4 months with placebo (HR, 0.32; P < .0001). For patients in the intention-to-treat population, the median PFS was 10.8 months in the rucaparib group versus 5.4 months with placebo (P <.0001).8

References:

  1. 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(19):4257-4261. doi: 10.1158/1078-0432.CCR-15-0887.
  2. 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(3):244-250. doi: 10.1200/JCO.2014.56.2728.
  3. 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(23):7165-7170. doi: 10.1158/1078-0432.CCR-17-1337.
  4. 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. doi: 10.1016/j.gyno.2017.08.022.
  5. 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.
  6. 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.
  7. 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.
  8. 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. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.

2 of 3
PER Pulse™ Recap

ADDRESSING CLINICAL CONSIDERATIONS ASSOCIATED WITH PARP INHIBITOR SELECTION

Some of the common class effects of PARP inhibitor therapy include anemia, fatigue, nausea, and vomiting. There are some differences among the safety profiles for the 3 approved PARP inhibitor agents. In Studies 19 and 42, the safety profile of approved olaparib capsules included anemia, diarrhea, fatigue/asthenia, and nausea and vomiting, which were generally mild in nature (grade 1 and 2).1,2 More severe adverse effects (AEs) included anemia, fatigue, and abdominal pain.1,2 For the capsule formulation used in SOLO2, anemia, fatigue, and nausea and vomiting were seen, with comparable tolerability to those AEs seen in earlier studies.3 In SOLO2, anemia was more severe than the other AEs and grade ≥3 neutropenia occurred in approximately 5% of patients.3 Fatigue should be screened for regularly, and when it is encountered, assessment for underlying causes should be undertaken.4 Moderate or worse fatigue may require pharmacologic or nonpharmacologic intervention, and PARP inhibitor dose modification or interruption may be necessary.4
In the NOVA study, common grade 3/4 AEs associated with the use of niraparib included anemia, neutropenia, thrombocytopenia, fatigue, and hypertension.5 Dyspnea across all grades and decreased appetite were more common in patients ≥70 years, while grade ≥3 anemia was more common.6 An increased risk of grade 3/4 thrombocytopenia may occur in patients who weigh less than 77 kg or have a baseline platelet count below 150,000/μL.7 For these patients, an up-front dose modification to 200 mg daily should be considered.8

In ARIEL3, the safety profile seen with the use of rucaparib was comparable with the AE profile seen in Study 10 and ARIEL2, including anemia, fatigue, nausea, and vomiting.9,10 In addition, 34% of patients receiving rucaparib in ARIEL3 experienced elevations in alanine transaminase and aspartate transaminase, with 10% experiencing grade 3 elevations.10 These were generally transient in nature and were not accompanied by elevations in bilirubin or any other signs of liver toxicity.10

With respect to concerns about the emergence of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with the use of PARP inhibitors, recent data have provided additional insight. In a post hoc analysis of SOLO2, these AEs occurred in 2.1% of patients treated with olaparib compared with 4% of patients treated with placebo.3,11 In NOVA, 1.4% of patients treated with niraparib developed MDS compared with 0.6% of patients treated with placebo; 1 patient treated with placebo developed AML.9 In ARIEL3, 1% of patients treated with rucaparib developed AML and MDS, while no patients treated with placebo developed these AEs.10 The incidence of AML and MDS may be associated with the number of prior lines of platinum therapy.11

References:

  1. 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.
  2. 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(3):244-250. doi: 10.1200/JCO.2014.56.2728.
  3. 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
  4. Moore KN, Monk BJ. Patient counseling and management of symptoms during olaparib therapy for recurrent ovarian cancer. Oncologist. 2016;21(8):954-963. doi: 10.1634/theoncologist.2015-0268.
  5. Mirza MR, Monk BJ, Herrstedt J, et al; and 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.
  6. Fabbro M, Moore KN, Dorum A, et al. Safety and efficacy of niraparib in elderly patients with recurrent ovarian cancer. Ann Oncol. 2017;28(suppl 5). academic.oup.com/annonc/article/28/suppl_5/mdx372/4109079.
  7. Moore KN, Mirza MR, Matulonis UA. The poly (ADP ribose) polymerase inhibitor niraparib: management of toxicities. Gynecol Oncol. 2018;149(1):214-220. doi: 10.1016/j.ygyno.2018.01.011.
  8. Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29(8):1784-1792. doi: 10.1093/annonc/mdy181.
  9. Colombo I, Lheureux S, Oza AM. Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer. Drug Des Devel Ther. 2018;12:605-617. doi: 10.2147/DDDT.S130809.
  10. 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 [erratum 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.
  11. Korach J, Turner S, Milenkova T, et al. Incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with a germline BRCA mutation and platinum-sensitive relapsed ovarian cancer receiving maintenance olaparib in SOLO2: Impact of prior lines of platinum therapy. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 5548. abstracts.asco.org/214/AbstView_214_218441.html.

3 of 3
PER Pulse™ Recap

DEVELOPING A ROAD MAP TO NEGOTIATE THE EXPANSION OF PARP INHIBITOR OPTIONS

Different techniques have been used to identify the presence of HRD, which has been associated with sensitivity to PARP inhibitor therapy. In addition to BRCA1 and BRCA2, several other genes have been associated with the homologous recombination pathway. Multiple germline mutations have been associated with tumor development, including RAD51, CHEK2, and ATM, and these mutations may have the potential to predict for the presence of HRD.1

Multiple guideline statements have recommended the pursuit of genetic sequencing for patients with ovarian cancer, regardless of patient age or tumor histology.2 Several genetic sequencing panels have emerged,3 and some data have addressed the question of whether somatic or germline testing should be pursued. Other assays to assess for HRD, beyond genetic sequencing, have been evaluated, including loss of heterozygosity (LOH). Genomic scars accumulate as a consequence of HRD and may be assessed as an extension of LOH.4

The challenge of acquired resistance to PARP inhibition in BRCA-mutated tumors remains a considerable one. Fundamental and preclinical research suggest that resistance to PARP inhibitors may be induced by mechanisms beyond genetic reversions that correct or bypass the original BRCA-inactivating mutation.5 Some of these mechanisms include drug efflux pumps, rewiring of the DNA damage response, and hypomorphic activity of mutant BRCA1 alleles.5

Two categories of therapy have garnered particular interest in combination with PARP inhibition: antiangiogenic agents and immunotherapy.6 Antiangiogenic agents may decrease the expression of genes and proteins used in the homologous recombination repair pathway, while the mutagenic burden induced by PARP inhibition may improve response to immunotherapy.

In studies that have examined the combination of PARP inhibition and immune checkpoint inhibitor therapy, patients with ovarian cancer have demonstrated considerable response. In the MEDIOLA study, patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer had a 12 week objective response rate (ORR) of 72% to the combination of olaparib and durvalumab, with a disease control rate of 81%.7 In the TOPACIO study, patients with platinum resistant/refractory ovarian cancer who were treated with the combination of niraparib and pembrolizumab had an ORR of 25%, with a disease control rate of 67% in the evaluable population.8

References:

  1. 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.
  2. National Comprehensive Cancer Network. NCCN Guidelines: ovarian cancer including fallopian tube cancer and primary peritoneal cancer. Version 2.2018. NCCN website. nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed July 19, 2018.
  3. Hall MJ, Obeid EI, 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. Colombo I, Lheureux S, Oza AM. Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer. Drug Des Devel Ther. 2018;12:605-617. doi: 10.2147/DDDT.S130809.
  5. Bouwman P, Jonkers J. Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors? Clin Cancer Res. 2014;20(3):540-547. doi: 10.1158/1078-0432.CCR-13-0225.
  6. Lorusso D, Fontanella C, Maltese G, et al. The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive ovarian cancer. Expert Opin Drug Saf. 2017;16(6):687-696. doi: 10.1080/14740338.2017.1325871.
  7. Drew Y, de Jonge M, Hong S-H, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer. Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. gynecologiconcology-online.net/article/S0090-8258(18)30833-3/abstract.
  8. Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/Keynote-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort. Presented at: 2018 ASCO Annual Meeting; June 3, 2018; Chicago, IL. abstracts.asco.org/214/AbstView_214_215001.html.






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