PARP Inhibitors Are Under Study as Treatment Options Beyond BRCA-Mutated Breast Cancer

Virginia G. Kaklamani, MD.

PARP inhibitors, including olaparib (Lynparza) and talazoparib (Talzenna), have changed the treatment paradigm for patients with BRCA-mutated breast cancer. However, further work must be done to see whether other subsets of patients can benefit from the use of PARP inhibitors, according to Virginia G. Kaklamani, MD.

“[We have] emerging data with [PARP inhibitors in] patients that have BRCA-like tumors. This is where a lot of work is being done, to see whether PARP inhibitors, either by themselves or in combination with immunotherapy or chemotherapy, might help improve outcomes in our patients,” Kaklamani said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

In the interview, Kaklamani, the chair of the IPC program, discussed the main takeaways from the meeting, which included the emerging role of PARP inhibitors, practice-changing updates in HER2-positive breast cancer, the utilization of CDK4/6 inhibitors in hormone receptor (HR)–positive, HER2-negative breast cancer, and the various therapeutic classes and their effects on care in triple-negative breast cancer (TNBC). Kaklamani is a professor of medicine in the Division of Hematology/Oncology at UT Health San Antonio, and the leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center.

OncLive^®: Marcela Mazo Canola, MD, of Mays Cancer Center at UT Health San Antonio, discussed HER2-positive breast cancer. What have been some of the key practice-changing updates in the early-stage setting?

Kaklamani: For early-stage HER2-positive breast cancer, 1 of the biggest updates is the data from the phase 3 KATHERINE trial [NCT01772472], which showed the patients who had [minimal] residual disease [MRD] after neoadjuvant chemotherapy benefited from the addition of ado-trastuzumab emtansine [T-DM1; Kadcyla] to their treatment instead of continuing trastuzumab [Herceptin]-based therapy.

Another pivotal trial was [the phase 3 APHINITY trial (NCT01358877), which examined] the addition of pertuzumab [(Perjeta) to trastuzumab and chemotherapy] in the adjuvant setting. [APHINITY] showed that for certain patient populations, adding pertuzumab to trastuzumab [and chemotherapy] improved their outcomes.

Based on these trials, the early-stage HER2-positive setting has changed such that most patients diagnosed with this type of disease are being cured.

What about practice-changing updates in the metastatic setting?

In the past 2 years, [there have been] several new drug approvals because of data from several pivotal clinical trials. The phase 2 HER2CLIMB trial [NCT02614794] looked at the addition of tucatinib [Tukysa] to [trastuzumab and capecitabine] and showed that tucatinib improves outcomes in patients with metastatic HER2-positive breast cancer, including patients with active brain metastases.

Another pivotal trial was the phase 3 DESTINY-Breast03 trial [NCT03529110], which is looking at the [use] of fam-trastuzumab deruxtecan-nxki [Enhertu], an antibody-drug conjugate [ADC], in the second-line setting. Results showed that trastuzumab deruxtecan improved outcomes compared with T-DM1.

We have some older clinical trials, such as the phase 3 CLEOPATRA trial [NCT00567190], which gave us a first-line standard-of-care therapy with a taxane, trastuzumab, and pertuzumab. Other drugs that have been shown to improve outcomes, such as margetuximab-cmkb [Margenza], are also approved and have changed how we treat our patients with HER2-positive breast cancer. [Margetuximab was approved based on] the data from the phase 3 SOPHIA trial [NCT02492711].

What parameters do you use to guide treatment decisions in early-stage HER2-positive breast cancer with the addition of these new therapies?

In the adjuvant or neoadjuvant setting, we have to re-stratify patients. We have to decide what the risk of recurrence is, and, right now, our ways of stratifying those risks have to do with clinical pathologic factors. How big is a tumor? Is there lymph node involvement? [Subsequent treatment decisions] also have to do with how well neoadjuvant chemotherapy has worked. If the chemotherapy has worked well, producing a pathologic complete response, then adjuvant therapy is more streamlined.

We still have a long way to go. There are other, more molecularly targeted ways of stratifying patients. We’re still not there yet. We still have to validate several of these assays to give us [a better] understanding of [which] patients have a higher risk of recurrence.

[For] some of the patients that have a higher risk of recurrence, we may need to add extended adjuvant therapy with neratinib [Nerlynx], as seen in the phase 3 ExteNET trial [NCT00878709]. For some patients, we may be able to give them single-agent antibody therapy with trastuzumab and a taxane. [It is important to treat] patients based on their risk and [to treat] them the right way. [We do not want to give] patients too much or too little treatment, but our goal is to cure all these patients.

What parameters do you use to guide treatment decisions with the addition of these new therapies in the metastatic setting?

In the metastatic setting, 1 of the factors that help us determine how to treat our patients is whether they have developed brain metastases. Tucatinib and other TKIs have shown good data in treating patients with brain metastases. Typically, we tend to favor tucatinib in that setting. If patients have not developed brain metastases, then an ADC, such as trastuzumab deruxtecan or T-DM1, might be a good option for these patients.

The important thing with metastatic HER2-positive breast cancer is looking at it as a chronic disease. These patients can survive for many years, and we must pace ourselves with treatment. We should not be extremely aggressive up front unless the patient seems to have very aggressive disease. [We need to realize] that these patients are going to be on treatment for many years to come, and, therefore, symptoms are extremely important to keep an eye out for because if we do give [patients] a lot of symptoms with their first- or second-line therapy, they may not have a good [enough] performance status to receive third-, fourth-, or fifth-line therapy.

You explored the emerging role of PARP inhibitors in your presentation. What have been some of the most notable advances with these agents, and what is being done to broaden their use beyond the BRCA-positive population?

In [2021], we [received] pivotal data from the phase 3 OlympiA trial [NCT02032823], which is looking at olaparib in the adjuvant setting. That study changed how we treat patients with BRCA1 or BRCA2 mutations [such that we now] give olaparib as long as they have a high enough risk to warrant that strategy.

In the metastatic setting, we have data from the phase 3 OlympiAD trial [(NCT02000622), which examined olaparib vs chemotherapy] and the phase 3 EMBRACA trial [NCT01945775], which looked at talazoparib [vs chemotherapy]. [These trials showed] that [PARP inhibitors] improve outcomes compared with single-agent chemotherapy. However, a small number of patients will be germline BRCA positive. Is there another subset of patients that might benefit from these drugs?

One of the subsets that may benefit from PARP inhibitors is patients with PALB2 mutations. Another subset of patients that seem to benefit from [PARP inhibitors] are those that have somatic mutations in the BRCApathway.

Kate Lathrop, MD, of the Mays Cancer Center at UT Health San Antonio, discussed HR-positive, HER2-negative breast cancer. What should be known with regard to treatment with CDK4/6 inhibitors in the metastatic and adjuvant settings?

In this field, CDK4/6 inhibitors are the big story and have been the big story since 2015, when [palbociclib (Ibrance)], the first CDK4/6 inhibitor, was approved. Recently, we’ve had some data in the metastatic setting that showed overall survival [OS] benefit with ribociclib [Kisqali] and some OS benefit with abemaciclib [Verzenio], as well.

In the adjuvant setting, recent data from the phase 3 monarchE trial [(NCT03155997) showed] that abemaciclib can help improve outcomes, and now abemaciclib [is] approved in the adjuvant setting.

There are other pathways, such as the PI3K pathway, where patients who have PIK3CA mutations may benefit from alpelisib [Piqray], given the results from the phase 3 SOLAR-1 trial [NCT02437318].

We have some older drugs such as mTOR inhibitors that we use. New data on oral selective estrogen receptor degraders [SERDs] show that we may be coming up with a different category of drugs altogether to use in that setting. One of the things that we’re still trying to tackle is endocrine resistance. Importantly, the most recent data with CDK4/6 inhibitors suggest that, especially when we use them in the first-line setting, patients can have an OS of more than 5 years, which is impressive, given the fact that up until a few years ago, OS in metastatic disease was around 2 years.

Heidi C. Ko, DO, of Mays Cancer Center at UT Health San Antonio, focused on TNBC. What therapeutic classes have had the greatest effect on current treatment standards in this space?

We have the emergence of immunotherapy, both in the early-stage and in the metastatic setting. The results from the phase 3 KEYNOTE-522 trial [NCT03036488] in the neoadjuvant setting suggest that there is long-term improvement in outcomes with the use of pembrolizumab [Keytruda]. In the metastatic setting, the use of pembrolizumab and atezolizumab [(Tecentriq) demonstrated] that in the subset of patients that have a PD-L1–positive tumor, there may be an improvement in OS and progression-free survival with the use of PD-1/PD-L1 inhibitors.

There is the emergence of ADCs, such as sacituzumab govitecan-hziy [Trodelvy], showing improvement in outcomes. More recently, there was a press release [on sacituzumab govitecan in] HER2-low breast cancer. Some of these HER2-low breast cancers can be estrogen receptor [ER] positive, but they can also be triple negative, suggesting that another ADC, trastuzumab deruxtecan, which we use in HER2-positive breast cancer, can also be active in the HER2-low subset. This is exciting because now we have more data in [the HER2-low] subset of breast cancer.

Looking at data from the OlympiA and KEYNOTE-522 trials, how would you approach patients with BRCA-mutant TNBC?

This is extremely difficult, and the same goes with the use abemaciclib, as well as olaparib, in patients with ER-positive breast cancer. Which 1 of the 2 agents do you pick? The answer is we don’t know. Many [clinicians] are combining these drugs, especially if we have safety data. Combining pembrolizumab with a PARP inhibitor and then continuing adjuvant pembrolizumab is relatively safe and may potentially be effective, especially in patients who have not achieved a pathologic complete response with neoadjuvant chemotherapy based on the KEYNOTE-522 trial. Adding a PARP inhibitor, olaparib in that case, may be beneficial. We don’t have the data with the combination [of pembrolizumab and olaparib], but most of us are doing this because these patients don’t have good outcomes.

In the ER-positive subset, we have patients who have high-risk disease but are also BRCA positive where you are struggling to determine whether to give olaparib or abemaciclib to these patients. I’ve used the approach of giving olaparib for 1 year, [followed by] abemaciclib for another 2 years, but, again, this is not based on any data. This is just based on extrapolating from different clinical trials.

Is there any ongoing or planned research at UT Health that you would like to highlight?

As in other malignancies, the addition of immunotherapy and more targeted agents has changed the landscape of how we treat breast cancer, improving outcomes and OS in our patients.

There are lot of new drugs approved and a lot of new drugs that come with their own toxicities. It is important for clinicians to understand how and when to use these drugs and when it’s worth using them, given the potential toxicities. Overall, this is a busy field and busy for good reason because we’re helping improve outcomes for our patients.

[Our] ongoing research [relates] to drugs looking at attacking breast cancer stem cells. We all know that cancers in general arise from stem cells, and there is a subset of agents, such as mTOR inhibitors, that can destroy stem cells. We have used that approach in patients with ductal carcinoma in situ, with the hope that these would be the type of agents to help prevent breast cancer altogether.

We are also doing work on patients with brain metastases with the use of sacituzumab govitecan in patients with brain metastases, as well as a radioactive particle in patients with leptomeningeal disease, trying to see whether this most aggressive type of brain recurrence can be treated with the use of radioactive isoforms.