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.
This activity is supported by educational grants from AstraZeneca, Clovis Oncology, Myriad Genetics Laboratories, and Tesaro Inc.
Release Date: August 15, 2018
Expiration Date: August 15, 2019
Media: Internet - based
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.
This activity is supported by educational grants AstraZeneca, Clovis Oncology, Myriad Genetics Laboratories, and Tesaro Inc.
Instructions for This Activity and Receiving Credit
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.
At the conclusion of this activity, you should be better prepared to:
Michael J. Birrer, MD, PhD
Comprehensive Cancer Center
Professor of Medicine, Ob/Gyn, and Pathology
University of Alabama at Birmingham
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
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
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
Director, Gyn Oncology Clinical Research
Co-Director, Gyn Oncology Phase I Program
James Cancer Center - Ohio State University
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.
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.
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®.
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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
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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
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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
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