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Community Practice Connections™: Translating Lessons Learned With PARP Inhibition to the Treatment of Breast Cancer – Expert Exchanges on Novel Strategies to Personalize Care PER Pulse™ Recap

PER Pulse Recap

PER Pulse™ Recap


 

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PER Pulse™ Recap

Understanding the Genetics – DNA Damage Response Defects and Role to Molecularly Define Tumor Subtypes

DNA damage response (DDR) is the reaction to endogenous and exogenous factors that create DNA single-strand and double-strand breaks. DDR involves multiple mechanisms that help to preserve genomic integrity.1 If there are any defects in the DDR pathway, as may occur in breast cancer, the concept of synthetic lethality emerges as a possible means of killing cancer cells.2 BRCA1 and BRCA2 play a role in double-strand break detection for the (HR) pathway. These genes are not functioning normally may lead to impaired homologous repair and tumorigenesis.

Significant responses to PARP inhibitor therapy have been observed in patients with germline BRCA (gBRCA) 1/2-associated breast and ovarian cancer. The quest to identify biomarkers that may predict breast cancer sensitivity to PARP inhibition is ongoing. Germline BRCA1/2 mutations are identified targets for PARP inhibitor treatment; however, PARP inhibitors have also demonstrated efficacy for some patients who do not have these mutations. These patients may carry a BRCA-like phenotype, with HR repair defects, and still respond to PARP inhibitor therapy.3 Patients may have pathway dysfunction due to somatic BRCA1/2, decreased expression (promoter methylation), or germline/somatic mutation in other pathway genes.

A variety of assays have been explored as possible means of predicting which patients may be likely to respond to PARP inhibitor therapy. Gene panels have been studied, but no current standard has been established. Assessment of telomeric allelic imbalances, along with loss of heterozygosity and large-scale transition, has been used to establish the presence of genomic scars that may act as biomarkers for DDR deficiency and responsiveness to PARP inhibitor therapy.4 In this segment, Dr. Domchek addresses the mechanism of PARP inhibitor therapy, genetic testing, and the concept of BRCAness.

References

  1. Murata S, Zhang C, Finch N, Zhang K, Campo L, Breuer EK. Predictors and modulators of synthetic lethality: an update on PARP inhibitors and personalized medicine. Biomed Res Int. 2016;2016:2346585. doi: 10.1155/2016/2346585.
  2. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109-8115.
  3. 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.
  4. Marquard AM, Eklund AC, Joshi T, et al. Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. Biomark Res. 2015;3:9. doi: 10.1186/s40364-015-0033-4.

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PER Pulse™ Recap

Historical Data Supporting the Use of PARP Inhibition

The emergence of the DDR pathway as a rational target for different types of cancer has led to the clinical development of PARP inhibitors. Several PARP inhibitors have demonstrated efficacy as monotherapy in clinical trials for patients with several types of cancer, including 3 PARP inhibitors that are currently approved for the treatment of patients with ovarian cancer.

Olaparib is approved for patients with gBRCA-mutated advanced ovarian cancer who have previously been treated with ≥3 lines of chemotherapy.1,2 Rucaparib has been approved for patients with germline and/or somatic BRCA-mutated ovarian cancer who have been treated with ≥2 chemotherapies. A key study presented the possibility of tumor loss of heterozygosity (LOH) as a means of identifying patients with platinum-sensitive BRCA wild-type ovarian cancers who might respond to rucaparib treatment. In this study, patients with BRCA-mutated or BRCA wild-type, LOH-high, platinum-sensitive ovarian cancer who were treated with rucaparib had a greater progression-free survival (PFS) than those with BRCA wild-type, LOH-low cancer.3 Niraparib has been approved for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. This approval was based on the results of the NOVA study.4

Several studies are being conducted to assess the role of PARP inhibition in patients with metastatic germline breast cancer, with some results recently published. Other studies are also being conducted that are assessing the role of PARP inhibitors in the treatment of early breast cancer. These include both the adjuvant and neoadjuvant settings. In this segment, Dr. Litton discusses the historical evidence supporting the use of PARP inhibitors in different types of cancer.

References

  1. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203. doi: 10.1016/j.ygyno.2015.12.020.
  2. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. doi: 10.1016/S1470-2045(14)70228-1.
  3. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9.
  4. 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.

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PER Pulse™ Recap

Translating Recent Clinical Trial Evidence on the Use of PARP Inhibition Into Practice: Current and Future Perspectives

Recent clinical trial evidence pertaining to the use of PARP inhibitors in the treatment of breast cancer may help to shape the treatment paradigm for patients with advanced and metastatic breast cancer with gBRCA mutations. Phase I and II studies have supported the role of PARP inhibitors in the treatment of these patients,1,2 including the recently presented results from the ABRAZO study.3 This phase II study assessed the efficacy of talazoparib in 84 patients who had advanced breast cancer with gBRCA mutations who previously had been treated with platinum (cohort 1) or ≥3 cytotoxic treatment regimens (cohort 2). Patients in cohort 1 had an overall response rate of 21% versus 37% in cohort 2.3 Results from the phase III OlympiAD study4 have recently been published and show that for patients with HER2-negative metastatic breast cancer with a gBRCA mutation, several outcomes were superior with treatment with olaparib compared with those treated with 1 of 3 standard chemotherapy regimens: capecitabine, eribulin, or vinorelbine. Risk of disease progression or death improved by approximately 42% for patients treated with olaparib (HR, 0.58; 95% CI, 0.43-0.80; P <.001).4 The duration of PFS was also greater in the group treated with olaparib (7.0 vs 4.2 months). For patients with measurable disease, the response rate was 59.9% in patients treated with olaparib compared with 28.8% of patients who received chemotherapy. Of note, olaparib was proved efficacious in patients with triple-negative breast cancer (TNBC) with gBRCA mutations.4

Several ongoing studies might expand the use of PARP inhibitors in the future. The BRAVO study5 is comparing the use of niraparib versus physician’s choice of 4 standard-of-care chemotherapy options in the treatment of patients with advanced and metastatic breast cancer with a gBRCA mutation. The phase III EMBRACA study6 is comparing the use of talazoparib versus physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine for the treatment of patients with BRCA-mutated, locally advanced, metastatic breast cancer. Olaparib is being assessed in the adjuvant setting in patients with germline BRCA-mutated, high-risk, HER2-negative, primary breast cancer in the phase III OlympiA study.7 The phase III BROCADE trial8 of veliparib/placebo combination with carboplatin and paclitaxel for patients with HER2-negative, metastatic or locally advanced, unresectable, BRCA-associated breast cancer is also underway. The study is open to patients with TNBC, as well as those with estrogen receptor-positive or progesterone receptor-positive disease. The potential application of PARP inhibitor therapy to patients with non‒BRCA-mutated breast cancer also has been studied, including patients with TNBC.

These and many other studies will help to answer questions regarding the use of different PARP inhibitors in the treatment of patients with metastatic gBRCA-mutated breast cancer, as well as potential application in patients who do not have gBRCA mutations. In this segment, Dr. Blackwell, Dr. Robson, and Dr. Traina discuss these key studies and potential applications to clinical practice.

References

 

  1. 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.
  2. 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.
  3. Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib following platinum or multiple cytotoxic regimens in advanced breast cancer patients with germline BRCA1/2 mutations. Presented at: the 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 1007.
  4. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation [published online June 4, 2017]. N Engl J Med. 2017. doi: 10.1056/NEJMoa1706450.
  5. A Phase III Trial of Niraparib Versus Physician's Choice in HER2 Negative, Germline BRCA Mutation-Positive Breast Cancer Patients (BRAVO). https://www.clinicaltrials.gov/ct2/show/NCT01905592. Updated April 10, 2017. Accessed August 1, 2017.
  6. A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study). https://www.clinicaltrials.gov/ct2/show/NCT01945775. Updated July 28, 2017. Accessed August 1, 2017.
  7. Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer. (OlympiA). https://www.clinicaltrials.gov/ct2/show/NCT02032823. Updated July 4, 2017. Accessed August 1, 2017.
  8. 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. https://www.clinicaltrials.gov/ct2/show/NCT02163694. Updated April 5, 2017. Ac




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