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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. These activites are not approved for AMA PRA Category 1 Credit™.

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Medical Crossfire®: Clinical Updates on PARP Inhibition and its Evolving Use in the Treatment of Cancers PER Pulse&trade Recap

PER Pulse Recap

PER Pulse™ Recap


1 of 3
PER Pulse™ Recap

 

DNA Damage Response Defects and the Path to Clinical Development of PARP Inhibitors

The 34th annual Miami Breast Cancer Conference®, held March 9 to 12, 2017, communicated state-of-the-art approaches for the management of patients with breast cancer, as well as emerging therapeutic paradigms. This first of 3 PER Pulse™ Recaps from the conference focuses on the mechanistic rationale for the development of PARP inhibitor therapy and assessment of clinical trial data from early studies of PARP inhibitor use in breast and ovarian cancer.

The DNA damage response involves multiple repair pathways that help preserve genome integrity. Poly (ADP-ribose) polymerases, or PARP, are a group of enzymes involved in this process. PARP-1 has been documented as having a key role in single-strand base excisional repair. Unrepaired single-strand breaks may cause replication forks to stall.1 This in turn leads to the emergence of double-strand breaks, which can lead to cell death if not fixed by homologous recombination.1 Homologous recombination is suboptimal in patients with BRCA-mutated cancers, because BRCA1 and BRCA2 proteins are key components of the homologous repair mechanism.2

Several early clinical trials assessed the role of PARP inhibition in the treatment in breast and ovarian cancer. A study conducted by Tutt and colleagues assessed the efficacy of olaparib as monotherapy for treating patients with advanced breast cancer and germline BRCA1/2 mutations.3 Patients who received 400 mg twice a day of olaparib had a 41% objective response rate.3 Gelmon et al assessed olaparib as monotherapy for treating high-grade serous ovarian cancer and triple negative breast cancer (TNBC). No confirmed responses were seen in the patients with TNBC, which the authors believe may be attributable to small sample size or the heavily pretreated nature of the patients involved.4 Kaufman and colleagues conducted a phase II study of olaparib therapy in patients with a variety of cancer types, including breast and ovarian, who had BRCA1/2 mutations.5 The response rate for breast cancer in this heavily pretreated population was 12.9%.5

Several phase III studies are addressing the role of PARP inhibition in the metastatic setting. The phase III OLympiAD study compared olaparib versus physician’s choice of capecitabine, vinorelbine, or eribulin for treating metastatic gBRCA breast cancer.6 Recent top-line results were reported in a press release, with more data to be presented at an upcoming medical meeting.7 The EMBRACA study is also assessing the role of PARP inhibition for treating patients with metastatic breast cancer, as well as those with locally advanced cancer. This phase III study compares talazoparib versus physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.8 The BRAVO study is assessing niraparib versus physician’s choice of 4 standard-of-care metastatic breast cancer chemotherapy options.9 The BROCADE 3 study is assessing the role of veliparib for treating patients with advanced/metastatic HER2-negative breast cancer.10

Even with these developments, several key questions remain regarding the use of PARP inhibition in the treatment of breast cancer. Future studies will help provide insight into which settings and combinations may optimize the use of PARP inhibitors.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 34th annual Miami Breast Cancer Conference®.

References

  1. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011;5(4):387-393. doi: 10.1016/j.molonc.2011.07.001.
  2. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi: 10.1186/s12916-015-0425-1.
  3. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235-244. doi: 10.1016/S0140-6736(10)60892-6.
  4. 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.
  5. 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. 
  6. Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer (OlympiA). clinicaltrials.gov/ct2/show/study/NCT02032823. Updated July 4, 2017. Accessed May 20, 2017.
  7. Olaparib meets primary endpoint in OlympiAD trial in BRCA-mutated metastatic breast cancer [news release]. The Asco Post; February 21, 2017. www.ascopost.com/News/48378. Accessed May 20, 2017.
  8. Litton J, Ettl J, Hurvitz SA, et al. A phase 3, open-label, randomized, 2-arm international study of the oral dual PARP inhibitor talazoparib in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA). Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract OT2-01-13.
  9. A phase III trial of niraparib versus physician’s choice in HER2 negative, germline BRCA mutation–positive breast cancer patients (BRAVO). clinicaltrials.gov/ct2/show/NCT01905592. Updated April 10, 2017. Accessed May 20, 2017.
  10. A phase 3 randomized, placebo-controlled trial of carboplatin and paclitaxel with or without veliparib (ATB-888) in HER2-negative metastatic or locally advanced resectable BRCA-associated breast cancer. clinicaltrials.gov/ct2/show/NCT02163694. Updated April 5, 2017. Accessed May 20, 2017.

2 of 3
PER Pulse™ Recap

 

Potential Expansions of PARP Inhibitor Therapy Beyond Germline BRCA Mutation

The 34th annual Miami Breast Cancer Conference®, held March 9 to 12, 2017, communicated state-of-the-art approaches for the management of patients with breast cancer, as well as emerging therapeutic paradigms. This second of 3 PER Pulse™ Recaps from the conference focuses on potential applications of PARP inhibitor therapy beyond patients with germline BRCA mutations.

Clinical investigation from the field of prostate cancer has yielded data of interest regarding the use of PARP inhibitors beyond patients with germline BRCA mutations. In a study conducted by Mateo and colleagues, several types of genomic abnormalities were associated with sensitivity of prostate cancer to olaparib. These mutations were observed in BRCA1, BRCA2, ATM, PALB2, CHEK2, FANCA, and HDAC2; all were reported to have a lethal interaction with PARP inhibition.1  The clinical relevance of these findings has yet to be determined. The concept of performing more extended testing in patients with breast cancer (eg, with focused panels looking at specific pathways) may be a way to identify other patients who may benefit from PARP inhibitor therapy.

The concept of “BRCAness” remains poorly defined. There has been clinical investigation into patient populations who have tumors that do not have germline BRCA mutations but still have at least putative defects in homologous recombination repair. Many methods have been proposed to look for these elements, which could theoretically be associated with sensitivity to platinum-based agents and PARP inhibition. Targeted sequencing, whole exome signatures, and “genomic scar” assessments have all been explored. One assay employs a combination of three DNA-based homologous recombination deficiency scores (LOH, TAI, and LST) which have been associated with response to platinum-based therapy and PARP inhibitors.2 In a study presented by Telli and colleagues, patients with TNBC (triple negative breast cancer) without BRCA mutations who had higher homologous recombination deficiency (HRD) scores were more likely to achieve a pathologic complete response with platinum-based neoadjuvant therapy than those with lower scores.3 The clinical utility of these findings remains under investigation, and other factors may need to be considered in guiding clinical therapy. In the TNT study, which assessed patients with advanced TNBC, high versus low HRD scores did not select for sensitivity of carboplatin over docetaxel.4 According to the panel, HRD scores may not capture elements needed to distinguish between docetaxel and carboplatin in the metastatic setting.

Studies in ovarian cancer, which are not necessarily directly applicable to guiding treatment for breast cancer, have provided interesting data. In the NOVA study, which assessed the efficacy of niraparib for treating patients with ovarian cancer, patients were grouped according to the presence or absence of a germline BRCA mutation. In the non-gBRCA group, patients with HRD who received niraparib had a greater median duration of progression-free survival (PFS) relative to placebo than those in the overall non-gBRCA cohort.5 Loss of heterozygosity has also been explored, along with BRCA1/BRCA2 mutations, as a means of predicting response to PARP inhibitor therapy. In the ARIEL2 study (part 1), patients with ovarian cancer who were BRCA wild-type and had LOH high platinum-sensitive ovarian cancer had a greater period of PFS than BRCA wild-type patients who had LOH low cancer.6 These findings point to the possibility of extending PARP inhibitor therapy beyond patients who have gBRCA mutations. Assessment of heterogeneity may be more challenging in patients with breast cancer, compared with those with ovarian cancer.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 34th annual Miami Breast Cancer Conference®.

References

  1. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708.
  2. Timms KM, Abkevich V, Hughes E, et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014;16(6):475.
  3. Telli ML, Timms KM, Reid J, et al. Homologous recombination deficiency (HRD) score as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): a pooled analysis. Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract P3-07-12.
  4. Tutt A, Cheang MCU, Kilburn L, et al. The TNT trial: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S3-01.
  5. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
  6. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian cancer (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87.

3 of 3
PER Pulse™ Recap

Future Directions and Combinations Involving PARP Inhibition

The 34th annual Miami Breast Cancer Conference®, held March 9 to 12, 2017, communicated state-of-the-art approaches for the management of patients with breast cancer, as well as emerging therapeutic paradigms. This third of 3 PER Pulse™ Recaps from the conference focuses on combination approaches and eagerly anticipated clinical trials pertaining to the use of PARP inhibitor therapy for breast cancer.

Several questions regarding the use of PARP inhibitors may be answered by ongoing clinical trials. PARP inhibitors as monotherapy have had limited study in untreated BRCA mutation carriers who have early stage breast cancer. Talazoparib is currently being studied in the neoadjuvant setting for these patients.1 It is also being investigated in a phase III study (EMBRACA) for patients with locally advanced and/or metastatic breast cancer versus physician’s choice of chemotherapy.2

The BROCADE 3 study is assessing the efficacy of carboplatin and paclitaxel with or without veliparib in patients with HER2-negative metastatic or locally advanced unresectable breast cancer.3 The SWOG S1416 study is exploring predictors of PARP inhibition, examining a population of patients with TNBC (triple negative breast cancer) and/or BRCA mutation–associated HER2-negative breast cancer with 0-1 prior lines of chemotherapy.4 In this study, patients are randomized to cisplatin and veliparib versus cisplatin and placebo. Many assays will be analyzed in the context of treatment response.4

The OlympiA study is assessing olaparib as adjuvant treatment in patients with germline BRCA-mutated, high-risk, HER2-negative primary breast cancer.5

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 34th annual Miami Breast Cancer Conference®.

References

  1. Litton JK, Scoggins M, Ramirez DL, et al. A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation. Presented at: ESMO 2016; October 8, 2016; Copenhagen, Denmark. Abstract 153PD.
  2. Litton JK, Blum JL, Im Y-H, et al. EMBRACA: A phase 3, open-label, randomized, parallel, 2-arm international study of the oral PARP inhibitor talazoparib (BMN 673) versus physician’s choice in BRCA mutation subjects with locally advanced and/or metastatic breast cancer. Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract OT1-03-16.
  3. A phase 3 randomized, placebo-controlled trial of carboplatin and paclitaxel with or without veliparib (ABT-888) in HER2-negative metastatic or locally advanced unresectable BRCA-associated breast cancer. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02163694. Updated April 5, 2017. Accessed June 11, 2017.
  4. Cisplatin with or without veliparib in treating patients with stage IV triple-negative and/or BRCA mutation-associated breast cancer. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02595905. Published November 3, 2017. Accessed June 11, 2017.
  5. Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer. (OlympiA). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02032823. First received/published January 3, 2014. Accessed June 11, 2017.




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