PARP Inhibition Explored in Triple-Negative Breast Cancer

Daniel P. Silver, MD, PhD

PARP inhibitors, which are a group of pharmacologic inhibitors of the enzyme poly ADP ribose polymerase (PARP), are gaining ground as a potential strategy for treating triple-negative breast cancer. The data are more promising in hereditary triple-negative breast cancer than for sporadic triple-negative breast cancer, but more research is needed, according to a presentation at the Chemotherapy Foundation Symposium held in New York City.

“It is still in the early days [of studying PARP inhibitors]. We still need results of clinical trials with veliparib, MK4827, and AGO14699, but research thus far suggests that PARP inhibition is likely to be active in hereditary triple-negative breast cancer,” stated Daniel P. Silver, MD, PhD, medical oncologist at the Breast Cancer Treatment Center at the Dana-Farber Cancer Institute, Boston, Massachusetts. However, Silver said, PARP inhibition is “not likely to be active as monotherapy in a large percentage of heavily pretreated sporadic triplenegative breast cancer, although biomarkers may identify a small subset that can benefit.”

PARP inhibition targets DNA repair in breast cancer by acting on the base excision repair DNA pathway, which acts in concert with the homologous recombination DNA repair pathway that requires BRCA1 and BRCA2, Silver explained. This provides the rationale for studying PARP inhibition in hereditary triple-negative breast cancer. BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer.

Early studies of PARP inhibitors in hereditary triple-negative breast cancer showed clinical benefit in carriers of BRCA1 and BRCA2. A recent phase II study of the PARP inhibitor olaparib in both sporadic and hereditary triple-negative metastatic breast cancer patients (Tutt A et al. Lancet. 2010;376(9737):235-244) showed the best responses in BRCA1 and BRCA2 carriers; 11 of 13 hereditary triple-negative patients had an overall response rate of 54%. “In this study, higher doses were better,” Silver commented.

“A number of investigators have found that sporadic and hereditary triple-negative breast cancer tumors share several characteristics, and they have posited that a deep relationship exists between these tumors. Sporadic triple-negative cancers appear to have a ‘BRCA-ness,’ meaning that something is wrong with the BRCA pathway,” Silver explained.

PARP inhibitors are also being studied in sporadic triple-negative breast cancer. A phase II trial of olaparib in advanced ovarian cancer and tripl-enegative breast cancer found no objective response in 16 sporadic cases, and that arm of the study was closed (Gelmon K et al. Lancet Oncology. 2011;12(9):852-861). Looking at a waterfall plot, which shows tumor shrinkage (not objective response rates), 63% of patients with BRCA1 or BRCA2 showed some tumor shrinkage and stable disease for more than 8 weeks, while only 13% of sporadic tumors had any degree of tumor shrinkage.

“Clearly, more large trials are needed, but it is unlikely that a proportion of metastatic, heavily pretreated sporadic triple-negative cancers will respond to PARP inhibitor monotherapy. It is entirely possible that there may be small subsets of patients identified by biomarkers that might respond,” Silver said.

Combinations of PARP inhibitors with chemotherapy are being studied as well. It appears that PARP inhibition may potentiate other chemotherapies, such as carboplatin, cisplatin, cyclophosphamide, and irinotecan, Silver commented.

Unexplored issues include the optimal rational combinations of therapy with PARP inhibitors, which are the best of these agents to combine with other therapies, timing, doses, and whether PARP inhibitors can act as radiosensitizers. Chemoprevention in carriers of BRCA1 and BRCA2 is an attractive option, but the safety of this approach needs to be established. PARP inhibitors in combination with chemotherapy or as part of other approaches may be useful in post-neoadjuvant therapy for triple-negative breast cancer patients who failed to achieve good response and are otherwise destined for poor outcomes.