Release Date: August 30, 2018
Expiration Date: August 30, 2019
Media: Internet - based
PER Pulse™ Recaps
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PER Pulse™ Recap
Overview of PARP Inhibitor Therapy and Rationale for Application in Breast Cancer
A great deal of progress has been made in the understanding of the mechanistic underpinnings for the use of poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor therapy in the treatment of patients with breast cancer. As the volume of evidence supporting the role of PARP inhibitors continues to accumulate, it is important for you to be able to apply clinical data to the development of treatment paradigms that maximize outcomes for your patients. This includes efficacy considerations, as well as development of strategies to identify and mitigate predictable treatment-related adverse events in a timely fashion.
To help you optimize the management of your patients with breast cancer, we have developed an exciting educational activity that will highlight the latest clinical evidence pertaining to the use of PARP inhibitors. This activity features commentary from leading experts in the management of patients with breast cancer, who will provide their perspectives on the rationale for PARP inhibitor utilization, key aspects of recent clinical studies, strategies to mitigate and manage predictable adverse events, and future directions for PARP inhibitor therapy.
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This educational activity is directed toward medical oncologists who treat patients with breast cancer. Nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of breast cancer are also invited to participate.
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Faculty, Staff, and Planners' Disclosure
Outline the mechanistic rationale that underlies the application of poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition approaches for the management of breast cancer
Apply key evidence from PARP inhibition trials in breast cancer, and report recent findings from investigations evaluating potential new roles for these approaches
Summarize strategies to mitigate predictable toxicities that have been reported with the use of PARP inhibition strategies
Identify strategies that are being explored to maximize the efficacy of PARP inhibition in the treatment of patients with breast cancer
Susan M. 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: Other: Honoraria: AstraZeneca, Clovis Oncology, Bristol-Myers Squibb.
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, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche, Puma Biotechnology, Merrimack Pharmaceuticals, Medivation, Dignitana, OBI Pharma, BioMarin, Cascadian Therapeutics; Other: Travel Support: Lilly, Novartis, OBI Pharma, Bayer.
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 Genetics, Medivation, Invitae; Consultant: AstraZeneca, McKesson.
Melinda L. Telli, MD
Assistant Professor of Medicine in the Division of Medical Oncology
Stanford University School of Medicine
Disclosure: Consultant: Celldex Therapeutics, G1 Therapeutics, Immunomedics, Merck, Pfizer, PharmaMar, Tesaro.
The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with commercial interests to disclose.
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A variety of genes have been implicated in familial breast cancer.1
Many of these genes, such as BRCA1
, are implicated in homologous recombination (HR). Patients with BRCA1
mutations have historically shown greater sensitivity to the use of PARP inhibitors than patients with wild-type or heterozygous BRCA1/2
In women who do not have the BRCA1
mutation, multigene sequencing evaluations have found that approximately 10% of patients possess another pathogenic germline mutation.4
This is important because DNA repair–targeted therapy may be relevant for patients who have non–germline BRCA1
) HR alterations.
A great deal of recent clinical investigation has been devoted to the identification of potential biomarkers of HR deficiency (HRD) in patients with cancer.5
These markers may reflect a state of “BRCAness,” where patients have a phenotype characterized by HRD without specific gBRCA1
mutations. Gene expression and mutational signatures of BRCAness have been explored, including assessment of potential “genomic scars” that correspond with genetic instability.5
Enzymes such as PARP 1 are involved in the repair of DNA single-strand breaks through an association with the process of base excision repair.6
When PARP inhibitors are utilized, there is an accumulation of single-strand breaks, which may lead to double-strand breaks and collapse of the replication fork if left unresolved. Homologous recombination is an important mechanism associated with the repair of DNA double-strand breaks. Such breaks can be extremely toxic to the cell, and they must be repaired efficiently and accurately. For patients with HRD, such as those with nonfunctional BRCA
genes, PARP inhibitor therapy can lead to the accumulation of double-strand breaks, which are not able to be repaired effectively, thus generating synthetic lethality for the cancer cell.6
Several PARP inhibitors have been developed, all with the capacity to efficiently and effectively inhibit the PARP enzyme.7
In addition to the inhibitory capacity of these agents, there has been clinical interest in the concept of PARP “trapping,” in which the PARP enzyme is complexed with DNA. These PARP-DNA complexes may accumulate, and are cytotoxic, thus potentially contributing to cancer cell death.7
For patients with HRD, such as those with nonfunctional BRCA genes, PARP inhibitor therapy can lead to the accumulation of double-stranded breaks, which are not able to be repaired effectively, thus generating synthetic lethality for the cancer cell.
Both catalytic inhibition and PARP trapping may contribute to the efficacy of PARP inhibitors in the treatment of patients with breast cancer.
1. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med. 2008;359(20):2143-2153. doi: 10.1056/NEJMra0802968.
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PER Pulse™ Recap
Recent Clinical Trial Evidence on PARP Inhibition and Clinical Application
2. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. DOI: 10.1038/nature03445.
3. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913-917. DOI: 10.1038/nature03443.
4. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014;32(19):2001-2009. doi: 10.1200/JCO.2013.53.6607.
5. Telli ML, Stover DG, Loi S, et al. Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer [published online May 7, 2018]. Breast Cancer Res Treat. 2018. doi: 10.1007/s10549-018-4807-x.
6. McLornan DP, List A, Mufti GJ. Applying synthetic lethality for the selective targeting of cancer. N Engl J Med. 2014;371(18):1725-1735. doi: 10.1056/NEJMra1407390.
7. Murai J, Pommier Y. Classification of PARP inhibitors based on PARP trapping and catalytic inhibition, and rationale for combinations with topoisomerase I inhibitors and alkylating agents. In: Curtin NJ, Sharma RA, eds. PARP Inhibitors for Cancer Therapy. New York: Springer International Publishing; 2015:261-274.
Two key phase III studies of PARP inhibition in the treatment of patients with metastatic breast cancer (MBC) have helped to shed light on the safety and efficacy of these treatment options. The OlympiAD study1
assessed a patient population with HER2
-negative, germline BRCA (
–mutated MBC, randomizing participants 2:1 to receive olaparib 300-mg tablets twice daily or a chemotherapy treatment of physician’s choice (TPC; capecitabine, eribulin, or vinorelbine). Patients with hormone receptor–positive (HR+) breast cancer were included if they had progressed on endocrine therapy or were not suitable for an endocrine-based approach. Patients who were treated with olaparib had a median progression-free survival (PFS) of 7.0 months compared with 4.2 months for patients in the chemotherapy arm (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P
=.0009). Data from the OlympiAD study led to the first approval of olaparib for patients with MBC.2
The EMBRACA study3
assessed a similar patient population, with HER2
-mutated, locally advanced breast cancer and MBC. This study had a similar design to the OlympiAD study, randomizing patients 2:1 to receive talazoparib 1 mg once daily or TPC chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). In this study, there were no limits on the previous number of lines of endocrine therapy. Patients with triple-negative breast cancer (TNBC) and HR+ breast cancer were eligible. Patients who were treated with talazoparib had a median PFS of 8.6 months compared with 5.6 months for those in the chemotherapy arm, with a similar hazard ratio to that seen in the OlympiAD study (HR, 0.54; 95% CI, 0.41-0.71; P
The safety data from OlympiAD were recently updated, with grade ≥3 adverse events (AEs) occurring at a rate of 38.0% in patients treated with olaparib in the final overall survival analysis compared with 49.5% of patients treated with TPC chemotherapy.4
Adverse events leading to drug discontinuation occurred in 4.9% of patients treated with olaparib compared with 7.7% treated with TPC chemotherapy.3
Dose interruptions were more common in patients treated with olaparib, whereas dose reductions were more common in patients treated with chemotherapy. Dose interruption could occur for a maximum of 4 weeks. The dose-reduction protocol involved initially lowering the dosage to 300 mg twice daily, with a further reduction to 200 mg twice daily, if necessary. No further dose reductions were allowed.4
In the EMBRACA study, patients who were treated with talazoparib experienced grade 3 anemia at a rate of 38.5% (grade 4: 0.7%), with a grade 3 neutropenia incidence of 17.8% (grade 4: 3.1%).3
Anemia was managed clinically, with only 2 patients needing to discontinue therapy due to anemia. Neutropenia was more common in patients treated with TPC chemotherapy. The only other grade 3 AEs reported with talazoparib that occurred at a rate ˃2% were vomiting, back pain, and dyspnea, at 2.4% each.
Multiple phase III studies have demonstrated the efficacy of different PARP inhibitors in the treatment of patients with HER2-negative, gBRCA-mutated, locally advanced breast cancer and MBC.
Recent safety updates have continued to support the tolerability of PARP inhibitor therapy for these patients.
1. 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(6):523-533. doi: 10.1056/NEJMoa1706450. [Erratum in: N Engl J Med. 2017;377(17):1700. doi: 10.1056/NEJMx170012.]
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PER Pulse™ Recap
Potential Approaches for Optimization and Expansion of PARP Inhibitor Therapy
2. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer [press release]. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm592357.htm. Updated January 12, 2018. Accessed January 29, 2019.
3. Litton JK, 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. cancerres.aacrjournals.org/content/78/4_Supplement/GS6-07.
4. Robson ME, Im SA, Senkus E, et al. OlympiAD final overall survival: olaparib versus chemotherapy treatment of physician’s choice in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation. Presented at the 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT038. cancerres.aacrjournals.org/content/78/13_Supplement/CT038.
Multiple studies are currently underway to assess different ways to enhance the efficacy of PARP inhibition for patients with breast cancer. One approach that has garnered recent interest is the combination of PARP inhibitors with conventional cytotoxic therapy, as was seen in the BROCADE 2 study.1
There are challenges with the combination of PARP inhibitors and conventional myelosuppressive agents due to the potential for overlapping myelotoxicities. Veliparib, a lower-potency PARP inhibitor, showed efficacy in combination with carboplatin/paclitaxel therapy with respect to median progression-free survival (PFS), but this was not statistically significantly greater than values seen with the combination of placebo and carboplatin.1
Other combinations that are being explored include PARP inhibitors and PI3K inhibitors. The rationale for this combination comes from the concept that PI3K inhibitors lower the nucleotide pools necessary for DNA synthesis and S-phase progression, thus increasing the sensitivity of breast cancer to PARP inhibition.2
PARP inhibitors have also been studied in combination with VEGF inhibitors, such as cediranib. PARP inhibitors have limited overlapping toxicities with antiangiogenic therapy, and the results of some studies have suggested a synergistic effect of PARP inhibition and antiangiogenic therapy.3
One area of great clinical interest is the combination of immunotherapy agents with PARP inhibition. The MEDIOLA study4
is assessing the combination of olaparib plus durvalumab. Patients have shown response to this combination, but the response attenuates with successive lines of therapy. The overall response rate in MEDIOLA was 67% in the first line compared with 60% with single-agent PARP inhibition.
Although PARP inhibition has been established in the treatment of metastatic disease, studies are also evaluating the use of PARP inhibition in earlier-stage disease. The OlympiA trial5
is an international study of the adjuvant use of olaparib in the treatment of patients with high-risk, HER2-negative, germline BRCA
)–mutated breast cancer. PARP inhibitor therapy is also being explored in the neoadjuvant setting. A recent feasibility study of neoadjuvant talazoparib for patients with operable gBRCA
-mutated breast cancer demonstrated marked activity, with a pathologic complete response rate ˃50%.6
Expansion of PARP inhibitor therapy to patient populations beyond those with gBRCA
-mutated breast cancer is also being studied. Patients who have homologous recombination deficiency (defined through various assays) may be susceptible to PARP inhibitor therapy. These patients who display this BRCAness phenotype who do not have a gBRCA
mutation may have pathway dysfunction due to a variety of sources, such as somatic BRCA1/2
mutation, decreased expression (promoter methylation), germline/somatic mutation in other pathway genes, and other undefined causes.7
Several commercially available assays have been developed, but have limitations.7
Multiple studies are currently underway assessing the combination of PARP inhibitors with other treatment modalities, such as VEGF inhibitors, chemotherapy, and immunotherapy for patients with breast cancer.
Studies are also examining the use of PARP inhibition in new lines of treatment for patients with breast cancer.
1. Han HS, Diéras V, Robson M, et al. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: a randomized, phase 2 study. Presented at the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S2-05. cancerres.aacrjournals.org/content/77/4_Supplement/S2-05.
2. Matulonis UA, Wulf GM, Barry WT, et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol. 2017;28(3):512-518. doi: 10.1093/annonc/mdw672.
3. Liu JF, Tolaney SM, Birrer M, et al. A phase 1 trial of the PARP 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.
4. Domchek SM, Postel-Vinay S, Bang Y-J, et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). Presented at the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017. San Antonio, TX. Abstract PD6-11.
5. Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer (OlympiA). clinicaltrials.gov/ct2/show/NCT02032823. Updated December 11, 2018. Accessed January 29, 2019.
6. Litton JK, Scoggins M, Ramirez DL, et al. A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. NPJ Breast Cancer. 2017;3:49. doi: 10.1038/s41523-017-0052-4.
7. Stover EH, Konstantinopoulos PA, Matulonis UA, Swisher EM. Biomarkers of response and resistance to DNA repair targeted therapies. Clin Cancer Res. 2016;22(23):5651-5660. DOI: 10.1158/1078-0432.CCR-16-0247.