Frequently Asked Questions on the Use of PARP Inhibitors to Treat Advanced Breast Cancer

Mark E. Robson, MD

Chief, Breast Medicine Service
Attending Physician
Clinical Genetics and Breast Medicine Services
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York


Mark E. Robson, MD, has disclosed that he has received funds for research support from AbbVie, AstraZeneca, BioMarin, and Medivation and consulting fees from AstraZeneca and McKesson.


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Released: January 10, 2019

Inhibitors of PARP, a key enzyme in the repair of single-stranded DNA breaks, are now an important treatment option for some patients with breast cancer. Olaparib is approved by the FDA for patients with HER2-negative metastatic breast cancer (MBC) and deleterious or suspected deleterious germline BRCA mutations who received previous chemotherapy for breast cancer. Similarly, talazoparib is approved by the FDA for patients with HER2-negative locally advanced breast cancer or MBC and deleterious or suspected deleterious germline BRCA mutations.This commentary is a selection of key questions about the optimal use of PARP inhibitors in the treatment of breast cancer asked by attendees during Clinical Care Options’ recent satellite symposium on this topic at SABCS 2018.

Given that PARP inhibitors are now approved for the treatment of HER2-negative MBC, should all women with HER2-negative breast cancer be tested for BRCA mutations?
Guidelines from the NCCN and other organizations now recommend quite broad testing for germline BRCA1/2 mutations in patients with HER2-negative breast cancer, particularly at diagnosis of unresectable locally advanced or metastatic disease. This is in line with the key phase III trials of olaparib and talazoparib being restricted to patients with HER2-negative locally advanced (talazoparib only) or metastatic disease and germline BRCA1/2 mutations and the corresponding FDA approvals. Some practices are now moving toward universal BRCA1/2 testing upon diagnosis of MBC, considering decreases in the costs of testing. That said, some patients are clearly less likely to have germline BRCA1/2 mutations, for example, a 75-year-old hormone receptor–positive patient with no family history of BRCA mutations.

In treating patients with MBC and germline BRCA1/2 mutations, should PARP inhibitors be used before or after platinum chemotherapy?
This is a common question. Because we do not have any head-to-head data comparing platinum agents with PARP inhibitors in first or later lines of therapy for patients with MBC and germline BRCA1/2 mutations, my approach is to base this decision on the clinical impact the disease is having on the patient. If the patient is not significantly symptomatic, my approach would be to start with a PARP inhibitor as these drugs are likely to be more tolerable and associated with better preservation of quality of life. The choice of a specific PARP inhibitor for individual patients comes down to toxicities and tolerability, as well as practical issues such as clinician familiarity and formulary availability, as the available agents appear to have similar efficacy. On the other hand, if a patient is sick with significant symptoms, I would instead recommend using a platinum agent first. The time to response is similar using either a PARP inhibitor or chemotherapy, but platinum treatment is “one shot”, while the PARP inhibitor requires continuous daily treatment. Although not really supported by clinical trial data, sensitivity to the platinum agent is likely to be a marker for sensitivity to a PARP inhibitor. So, if the patient achieves a good response to 3-4 cycles of a platinum agent with a decrease in symptoms, she may be switched to a PARP inhibitor for disease control, as is done in the setting of ovarian cancer.

Should PARP inhibitors be used in the treatment of patients with HER2-positive MBC and germline BRCA1/2 mutations?
No clinical data exist to support using PARP inhibitors in HER2-positive breast cancer, but nevertheless, this is an off-label option in many centers. A HER2-positive tumor with a germline BRCA mutation would likely still have the same sensitivity to PARP inhibition as a HER2-negative tumor. However, given the excellent results of HER2-targeted therapy, I would take an approach similar to how I sequence PARP inhibition with endocrine therapies in patients with hormone receptor–positive MBC: Exhaust the effective HER2-targeted agents before moving to a PARP inhibitor. I would not choose a PARP inhibitor over an available, effective HER2-directed therapy.

Is there any evidence that PARP inhibitors may be able to target germline mutations in other DNA repair genes?
Although there are ongoing clinical trials evaluating whether PARP inhibitors may be able to target mutations in DNA repair genes beyond BRCA1/2, we simply do not have data yet on which, if any, of these other DNA repair genes may be predictive of PARP inhibitor sensitivity and, therefore, be a clinically useful biomarker to guide the use of PARP inhibition. Given the lack of data to support this choice, I would not recommend a PARP inhibitor to treat a patient with a non-BRCA1/2 mutation (such as PALB2) outside of a clinical trial at this moment. Moreover, even if non-BRCA mutations in DNA repair genes are identified in the tumor of a particular patient, the degree of that sensitivity to PARP inhibition may be different than what we see with BRCA1/2 mutations. For example, in the setting of prostate cancer, results from the phase II TRITON2 study showed that patients with alterations in ATM do not appear to benefit greatly from rucaparib, whereas rucaparib is clearly active against BRCA2 mutations. Patients with breast cancer and mutations in DNA repair genes other than in BRCA1/2 should be enrolled onto clinical trials such as the ongoing phase II study of olaparib in patients with previously treated MBC and mutations in ATM, CHEK2, PALB2, and other homologous recombination–related genes, excluding BRCA1/2

Your Thoughts
Have you started using PARP inhibitors in the treatment of breast cancer? Share your experiences in the comment box below.

To see what 5 experts would recommend for patients with MBC in different clinical scenarios, visit the Interactive Decision Support Tool: Treatment for Metastatic Breast Cancer.
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This activity is supported by educational grants from
AstraZeneca
Pfizer Inc.
Tesaro

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