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Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?
Release Date: May 31, 2018
Expiration Date: May 31, 2019
Media: Internet - based
Information pertaining to the applications of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the treatment of patients with breast cancer continues to emerge at a rapid pace, with multiple phase III studies yielding important safety and efficacy data. As clinicians who treat patients with breast cancer, it is imperative for you to have a solid understanding of the mechanistic rationale for the use of these medications. It is also important for you to be aware of methods that are being studied to help you optimize patient selection for PARP inhibitor therapy, personalize breast cancer treatment approaches for your patients, and mitigate potential treatment-related adverse events.
To help you meet these goals, we have developed an educational activity that features video commentary from leading experts in the management of patients with breast cancer, who will address multiple topics pertaining to the potential use of PARP inhibitors in the treatment of patients with breast cancer.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from AstraZeneca.
Instructions for This Activity and Receiving Credit
This activity is directed toward medical oncologists who treat patients with breast cancer. Nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other health care professionals interested in the treatment of breast cancer are invited to participate.
At the conclusion of this activity, you should be better prepared to:
- Explain the mechanistic rationale for the use of PARP inhibition in the treatment of cancer and strategies to optimize patient selection for this therapy
- Analyze historical evidence pertaining to the use of PARP inhibition in ovarian and breast cancers
- Examine evolving efficacy and safety data concerning the application of PARP inhibitors in the treatment of ovarian and breast cancers, including how this information may inform personalized treatment and mitigation of treatment-related toxicities
- Summarize key ongoing studies that address expansion of PARP inhibitor use in different settings for patients with breast cancer
Faculty, Staff, and Planners' Disclosures
Kimberly L. Blackwell, MD
Professor of Medicine
Assistant Professor of Radiation Oncology
Duke University Medical Center
Disclosure: Grant Research Support: Celgene, Genentech, Pfizer, Novartis; Consultant: Astra Zeneca, Celgene, Celltrion Healthcare, Celldex Therapeutics, Eisai, Eli Lilly, Genentech, Mylan GmbH, Novartis, Pfizer, Pierian Biosciences, Puma, Roche, Syndax, Visante, Seattle Genetics
Susan Domchek, MD
Director, MacDonald Women’s Cancer Risk Evaluation Center
Executive Director, Basser Center for BRCA
Basser Professor in Oncology
Perelman School of Medicine
University of Pennsylvania
Disclosure: Honoraria: AstraZeneca, Clovis, BMS.
Sara A. Hurvitz, MD
Associate Professor of Medicine, Division of Hematology/Oncology
Director, Breast Cancer Clinical Research Program
Co-Director, Santa Monica–UCLA Outpatient Hematology/Oncology Practice
David Geffen School of Medicine at UCLA
Santa Monica, CA
Disclosure: Grant Research Support: Amgen, Bayer, BI Pharma, Genentech, GSK, Lilly, Novartis, Pfizer, Roche, Puma, Merrimack, Medivation, Dignitana, OBI Pharma, Biomarin, Cascadian; Travel Support: Lilly, Novartis, OBI Pharma, Bayer.
Jennifer K. Litton, MD
Department of Breast Medical Oncology and Clinical Cancer Genetics
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Disclosure: Grant Research Support: Pfizer, AstraZeneca, Genentech, GSK, EMD Serono; Consultant: Advisory Boards: Pfizer; AstraZeneca – uncompensated.
Mark E. Robson, MD
Chief, Breast Medicine Service
Attending Physician, Breast Medicine and Clinical Genetics Services
Professor of Medicine, Weill Cornell Medical College
Memorial Sloan Kettering Cancer Center
New York, NY
Disclosure: Grant Research Support: AstraZeneca, AbbVie, Myriad, Medivation, Invitae; Consultant: AstraZeneca, McKesson.
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
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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™ Recaps
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PER Pulse™ Recap
Overview of PARP Inhibition, Synthetic Lethality, and Treatment Resistance
The identification of BRCA1 and BRCA2 proteins as key factors in the repair of double-strand breaks in DNA has led to the development of paradigm-shifting approaches to the treatment of patients with breast cancer. Mutations in BRCA1 and BRCA2 are found in approximately 10% of patients with triple-negative breast cancer (TNBC) and 5% of all breast cancers.1 These genes normally encode proteins that facilitate the repair of double-strand breaks in DNA through the homologous recombination (HR) pathway. For those patients who have mutations in BRCA1 and BRCA2, there may be a deficiency in homologous recombination (HRD), requiring cells to utilize the less-effective nonhomologous end-joining pathway to repair double-strand breaks.
Poly (ADP-ribose) polymerase (PARP) enzymes 1 and 2 are key factors in the repair of single-strand breaks in DNA. Single-strand breaks prompt the activation of PARP enzymes, which facilitate base excision repair. PARP recruits other DNA repair proteins.2 When PARP inhibitors are employed, single-strand breaks remain unrepaired, leading to stalled replication forks and double-strand breaks.2 For cells that do not have an effective means of repairing double-strand breaks, such as those with BRCA-mutated cancers and impaired HR repair, this leads to tumor cell death.2
In addition to catalytic inhibition, PARP inhibition may also result in the development of PARP “trapping,” where PARP inhibitors “trap” PARP proteins on damaged DNA, forming complexes that are toxic to the tumor cell.3 PARP inhibitors differ with respect to their ability to create catalytic inhibition and to trap PARP. Talazoparib is the most potent agent for PARP trapping, although niraparib, olaparib, and rucaparib also have this capacity.4,5
A variety of other mechanisms have been proposed to account for innate or acquired resistance, including genetic reversion, epigenetic reversion, hypomorphic alleles, loss of PARP1 expression, loss of end resection regulation, trans-lesion synthesis activation, upregulation of p-glycoprotein efflux pumps (which may lower PARP inhibitor levels), and extensive desmoplastic stromal reaction.6 A variety of methods to address the development of resistance to PARP inhibition are currently being investigated.
· The understanding of how PARP inhibitors function in the treatment of patients with breast cancer continues to evolve, with components of catalytic inhibition and the “trapping” of PARP proteins proposed to account for their efficacy.
· Several factors may contribute to emergence of resistance to PARP inhibitor therapy, which are being investigated in ongoing studies.
1. Griguolo G, Dieci MV, Guarneri V, Conte P. Olaparib for the treatment of breast cancer [published online March 30, 2018]. Expert Rev Anticancer Ther. 2018. doi: 10.1080/1474=37140.2018.1458613.
2. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5:387-393. doi: 10.1016/j.molonc.2011.07.001.
3. Isakoff SJ, Puhalla S, Domchek SM, et al. A randomized phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale. Future Oncol. 2017;13(4):307-320. doi: 10.2217/fon-2016-0412.
4. Murai J, Huang SY, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014;13:433-443. doi: 10.1158/1535-7163.MCT-13-0803.
5. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72:5588-5599. doi: 10.1158/0008-5472.CAN-12-2753.
6. Konstantinopoulos PA, Ceccalsi R, Shapiro 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.
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PER Pulse™ Recap
Translating Recent Clinical Trial Evidence on the Use of PARP Inhibition Into Practice
The US Food and Drug Administration (FDA) has approved 2 PARP inhibitors for the treatment of patients with breast cancer, beginning with olaparib tablets for the treatment of patients with gBRCA-mutated, HER2-negative metastatic breast cancer (MBC) who have received chemotherapy in the adjuvant, neoadjuvant, or metastatic setting.1 This approval was based on the results of the phase III OlympiAD study,2 which randomized patients with gBRCA-mutated, HER2-negative MBC who had received ≤2 previous lines of chemotherapy in the metastatic setting to olaparib 300 mg twice daily or chemotherapy treatment of physician’s choice (TPC), including capecitabine, eribulin, or vinorelbine. The primary endpoint of this study was progression-free survival (PFS); patients who received olaparib had a median PFS of 7.0 months compared with 4.2 months in patients receiving chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P =.0009).
The EMBRACA study3 compared talazoparib versus TPC (capecitabine, eribulin, gemcitabine, or vinorelbine) for the treatment of patients with locally advanced or gBRCA-mutated, HER2-negative MBC. The primary endpoint of this study was also PFS; patients treated with talazoparib had a median PFS of 8.6 months compared with 5.6 months in patients receiving chemotherapy (HR, 0.54; 95% CI, 0.41-0.97; P <.0001). This benefit was seen across multiple subgroups, including stratification factors such as number of prior chemotherapy regimens (0 or ≥1), receptor status (triple-negative or hormone receptor‒positive breast cancer), and history of central nervous system metastases (present or not). This study has also led to the FDA approval of talazoparib.
In the OlympiAD study, dose reduction was most commonly due to anemia, and 4 patients (2.0%) had to discontinue treatment due to anemia.2 In the EMBRACA study, anemia was also quite common, and 2 patients (0.7%) had to discontinue talazoparib due to anemia.3 Alopecia was also noted with talazoparib use (25.2% of patients) compared with 27.8% of patients receiving TPC; however, the vast majority of cases in patients treated with talazoparib were mild (grade 1).3
· Multiple PARP inhibitors have been approved for the treatment of patients with MBC, with improvements in PFS seen for both olaparib and talazoparib.
· Anemia is among the common adverse events associated with PARP inhibition, with only a small percentage of patients requiring treatment discontinuation.
1. US Food and Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm592357.htm. Updated January 12, 2018. Accessed January 28, 2019.
2. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-533. doi: 10.1056/NEJMoa1706450.
3. Litton J, Rugo HS, Ettl J, et al. EMBRACA: a phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. Presented at the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.
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PER Pulse™ Recap
Potential Expansion of PARP Inhibition Strategies
PARP inhibition has demonstrated efficacy in the treatment of patients with BRCA-mutated breast and ovarian cancer, and emerging data are assessing the efficacy of PARP inhibition in a variety of patient populations. The OlympiA study1 is assessing the safety and efficacy of adjuvant olaparib therapy in patients with BRCA-mutated triple-negative breast cancer (TNBC) or hormone receptor–positive/HER2-negative breast cancer. Enrolled patients will have received definitive local treatment and neoadjuvant chemotherapy or adjuvant chemotherapy. The primary endpoint of this study is invasive disease-free survival. Secondary endpoints include distant disease survival and overall survival.1
PARP inhibition in BRCA1/2-mutated breast cancer is being studied in a wide range of combinations, including those with hormonal therapy, immunotherapy, or other targeted therapy. The MEDIOLA study2 is assessing the combination of olaparib plus durvalumab in the treatment of patients with advanced solid tumors. Data for patients with HER2-negative, gBRCA-mutated metastatic breast cancer (MBC) who were treated with this combination were presented at the 2017 San Antonio Breast Cancer Symposium. For these patients, the disease-control rate at 12 weeks was 80%, suggesting the possibility that the addition of durvalumab may enhance the efficacy of olaparib monotherapy.2
Another study assessing the combination of PARP inhibition with programmed death ligand-1 (PD-L1) inhibition is the KEYNOTE-162 study.3 In this study of heavily pretreated patients with TNBC or recurrent ovarian cancer, the combination of niraparib plus pembrolizumab demonstrated efficacy, and a phase II study assessing the combination is underway. Many other combinations using PARP inhibitors are being studied, including pairing with ataxia telangiectasia and Rad3-related (ATR) inhibitors. Clinical investigation has shown that BRCA1-deficient (mutated) cells are often dependent upon ATR to survive.4 ATR inhibition may be able to interfere with RAD51 loading to DNA double-strand breaks in PARP inhibitor‒resistant cells that are BRCA1-deficient.4 Other PARP combinations that have been studied in the treatment of patients with breast cancer include those involving Wee1 inhibitors, as well as antiangiogenic agents.5,6
· The foundation of PARP inhibition in patients with BRCA-mutated breast and ovarian cancer is established, and ongoing studies are evaluating PARP inhibitors in different lines of therapy.
· New combinations of PARP inhibition with other classes of therapy are being evaluated for patients with breast cancer.
1. Tutt A, Kaufman B, Gelbert RD, et al. OlympiA: a randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(15 supp; abstr TPS1109).
2. Domchek SM, Postel-Vinay S, Bang YJ, et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated HER2-negative metastatic breast cancer. Presented at the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX; Abstract PD6-11.
3. Konstantinopoulos PA, Sachdev JC, Schwartzberg L, et al. Dose-finding combination study of niraparib and pembrolizumab in patients with metastatic triple-negative breast cancer or recurrent platinum-resistant epithelial ovarian cancer (TOPACIO/KEYNOTE-162). Ann Oncol. 2017;28 (suppl 5; abstr 1143PD). doi: 10.1093/annonc/mdx376.009.
4. Yazinski SA, Comallis V, Buisson R, et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev. 2017;31(3):318-332. doi: 10.1101/gad.290957.116.
5. Do K, Wilsker D, Ji J, et al. Phase I study of single-agent AZD1775 (MK-1775), a Wee 1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol. 2015;33(30):3409-3415. doi: 10.1200/JCO.2014.60.4009.
6. Liu JF, Tolaney SM, Birrer M, et al. A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013;49(14):2972-2978. doi:10.1016/j.ejca.2013.05.020.
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