Role of PARP Inhibitors in Triple-Negative Breast Cancer

Judy Garber, MD, MPH

As part of our coverage of the 2017 European Society for Medical Oncology (ESMO) Congress, held September 8-12 in Madrid, Spain, we are speaking with Dr. Judy Garber, professor of medicine at Harvard Medical School and director of the Center for Cancer Genetics and Prevention, who focuses on breast cancer at the Dana-Farber Cancer Institute. Dr. Garber gave a talk at an educational session at the congress on PARP inhibitors for triple-negative breast cancer.

                  -Interviewed by Anna Azvolinsky

Oncotherapy Network: Can you talk about PARP inhibitors in general? What are these drugs, and what do they target?

Dr. Garber: PARP inhibitors inhibit the poly (ADP-ribose) polymerase (PARP) enzyme, which is an important enzyme in the repair of DNA errors. The original work on PARP inhibitors came from researchers who studied DNA repair, such as Alan Ashworth, PhD, FRS, in the United Kingdom. They realized that if the PARP enzyme was blocked, there would be breaks in the DNA that could not be well repaired, and those breaks might kill cancer cells. So, researchers looked for cells that would be unable to repair errors after the PARP inhibitor caused them. When you think about chemotherapy in general, there are mistakes and breaks that occur in the DNA all the time. When it’s effective, it is often because those breaks are fatal to the cell, and there are so many breaks that the cells can’t recover. Tumors that lack either BRCA1 or BRCA2 are good targets for PARP inhibitors. Most breast and ovarian cancers do not have mutations in the BRCA1 or BRCA2 genes. When tumors develop in people who have inherited mutations in one copy of their BRCA1 or BRCA2 genes in all of their cells, including in their normal breast or ovary, these tumors have often lost the second normal copy and are missing functioning BRCA1 or BRCA2, and, therefore, are particularly susceptible to killing by PARP inhibitors.

There is a second mechanism of action in which the PARP enzyme can be trapped on the DNA, trying to repair the DNA breaks caused by the PARP inhibitors. The PARP enzyme is in the way and the DNA is not repaired, and that can cause cells to die. We think that may explain why even people who do not have a germline mutation or are not born with mutations in either BRCA1 or BRCA2 can still have tumors that are susceptible to killing by PARP inhibitors. If you look at ovarian cancer, for example, there is activity even in women who do not have these mutations, and that speaks to the biology of ovarian cancer, which is similar to BRCA1- or BRCA2-deficient tumors. In breast cancer, however, that has generally not been the case. Most often, people with inherited mutations in BRCA1 or BRCA2 are susceptible to PARP inhibitors, although not exclusively.

OncoTherapy Network: What do we know about how PARP inhibitors work in triple-negative breast cancer patients? Is it only a subset of triple-negative disease that may be susceptible to PARP inhibitor treatment?

Dr. Garber: Primarily, PARP inhibitors have been studied in patients with triple-negative breast cancer who have a BRCA1 or BRCA2 mutation. The original work from Karen Gelmon, MD, of the BC Cancer Agency in Vancouver, showed that those were the breast cancers that would be sensitive to killing by PARP inhibitors, rather than tumors that did not carry those germline mutations. One of the first studies that had been done, the so-called ICEBERG trial led by Andrew Tutt, PhD, from King’s College London School of Medicine in the United Kingdom, used olaparib for those with BRCA1 or BRCA2 mutations. About 40% of patients with metastatic disease and a germline BRCA1 or BRCA2 mutation responded to the agent even after pretty significant pretreatment. This was true for both triple-negative and estrogen receptor (ER)-positive patients. Current guidelines indicate that patients with triple-negative breast cancer should be tested to see if they carry a BRCA1 or BRCA2 mutation, as long as they are diagnosed under age 60 or have a family history of breast cancer. We are identifying carriers, but we haven’t had great options for these patients.

There are some other tests that have tried to identify what is called “BRCAness”; that is, identifying breast tumors that might behave like BRCA1- or BRCA2-deficient tumors even if they occur in someone without a mutation. Earlier tests, such as homologous recombination deficiency and others like it, have not been very successful in predicting response to PARP inhibitors. A recent test called HRDetect was looked at in 560 samples and it was actually quite efficient in identifying the responders among patients with triple-negative breast cancer. What was so interesting was that the test identified those patients who knew they had BRCA1 or BRCA2 mutations when they entered the study, but it also identified people with the mutations who had not been previously tested and did not know that they had these inherited mutations in their germline. In addition, the researchers found responders among patients who did not have inherited mutations but whose tumors had a somatic or acquired mutation in BRCA1 or BRCA2. Patients who had a mutation but did not lose the second copy did not respond to PARP inhibitors, but those with either an inherited mutation or those whose tumor had developed a mutation did respond. This suggests, perhaps, that PARP inhibitors will have some activity beyond those with inherited risk.

OncoTherapy Network: Are there any clinical trials that you could highlight that are testing PARP inhibitors for triple-negative breast cancer patients beyond those who have inherited BRCA1 or BRCA2 mutations?

Dr. Garber: In breast cancer trials so far, investigators have mainly focused on those with BRCA1 or BRCA2 mutations. The two studies reported at the American Society of Clinical Oncology (ASCO) Annual Meeting this year are particularly important because they are likely to be on the path to approval. There have been many studies of PARP inhibitors-mostly small studies-in patients with prior treatment and sometimes in combination therapy, but these studies presented at ASCO were single-agent trials of patients with first- or second-line recurrence of breast cancer. These patients did not all have triple-negative disease, but they were all BRCA1 or BRCA2 carriers.

The first was the OlympiAD trial of the PARP inhibitor olaparib compared with one of three chemotherapy drugs-capecitabine, eribulin, or vinorelbine. All patients included were BRCA mutation carriers and had one or two prior treatments for metastatic disease. The study showed a significant progression-free survival advantage with olaparib; there was no overall survival benefit from the drug, however. The researchers looked at triple-negative and ER-positive patients and observed that the benefit was confined to the triple-negative patients. Patients who had prior platinum therapy as part of their treatment did not benefit, whereas those who did not have prior platinum treatment had more of a benefit. It is important to note that these were pretty small subsets of patients, so we don’t want to over interpret these findings. As for toxicity, the advantage was in favor of olaparib vs the chemotherapy drugs. One of the sobering parts of the study, however, was that a large group of collaborators was needed to enroll only a few hundred patients.

The ABRAZO trial looked at the PARP inhibitor talazoparib and compared it with other physician choice single agents. In this study, there was also a benefit in BRCA1 and BRCA2 carriers. This trial had two cohorts: the first included patients who had received prior platinum treatment, and the second cohort had not had prior platinum treatment. One issue to note is that for the group that had prior platinum therapy, the longer the interval from the prior platinum, the better the patients did. There was really no benefit when they were less than 2 months from treatment, but they did have benefit when they were at least 6 months from treatment. An even greater benefit was observed in the group that had not had prior platinum therapy. Compared with the OlympiAD trial, there was a benefit in the ER-positive patients as well. Because BRCA2 mutation carriers are more likely to have ER-positive disease, this suggests that they can still benefit from PARP inhibitors. There are ongoing trials for all five PARP inhibitors currently under development: olaparib, niraparib, talazoparib, rucaparib, and veliparib.

OncoTherapy Network: Lastly, are there any ongoing trials with PARP inhibitors that you and your colleagues are anticipating for patients with triple-negative disease?

Dr. Garber: The OlympiA trial is studying individuals with triple-negative breast cancer or ER-positive high-risk breast cancer with four or more positive nodes, who are carriers of BRCA1 or BRCA2 and have completed prior treatments, to test if adjuvant olaparib for 1 year vs placebo will offer a survival advantage. This trial will complete accrual next year and should have data by 2020, so that is an exciting development for these drugs. The future of PARP inhibitors is probably going to be in combination therapy, the most exciting of which is with immunotherapy. Combination therapies are a natural next step because the PARP inhibitors are busy causing DNA breaks and creating new antigens in the tumors, which creates targets for immunotherapy. There are a number of ongoing neoadjuvant and combination trials that are already presenting preliminary results at meetings. So, there will hopefully be more activity yet to come.