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.

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.

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].

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. Were 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.

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.

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.

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, weve 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 were 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.

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-L1positive 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.

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 dont 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 dont have the data with the combination [of pembrolizumab and olaparib], but most of us are doing this because these patients dont 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. Ive 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.

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 its worth using them, given the potential toxicities. Overall, this is a busy field and busy for good reason because were 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.

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

Winning an award is nice, of course, but thats only a small reason to do a science fair project. Theres learning about science, how to conduct an experiment and working with others to achieve a goal. And competing itself is its own reward, say alumni of the International Science and Engineering Fair, or ISEF.

This week, more than 1,700 teens have gathered online and in Atlanta, Ga., for the 2022 Regeneron ISEF. These high-school students have competed in science fairs across the globe for the right to show off their work. Now theyre vying for nearly $8 million in scholarships and other prizes. (This annual competition is held by the Society for Science, which also publishes Science News for Students.)

To get a bit of insight into the ISEF experience, Science News for Students spoke with four recent competitors. Heres what they said about competing in the so-called Olympics of science fairs.

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Jacob competed in ISEF from 2015 to 2018. For his projects, he revamped a 3-D printer to print with multiple materials and optimized inks to print electronics and solar cells. He now works at the 3-D printing company Inkbit, which is based in Medford, Mass.

How would you describe ISEF?

Id definitely compare it to the Olympics of science fair, Jacob says. But its not just a science fair, he adds. Its an incredible social experience for like-minded high schoolers who are interested in science research. The week of ISEF is full of opportunities to socialize such as a dance party and a massive pin exchange between competitors. You get to meet people from all over, Jacob says. You have a lot of fun just going to different activities and exploring interests and having interesting conversations with other people your age.

What makes a good science fair project?

One of the biggest things is just picking a topic that you find interesting, Jacob says. Some students will try to do something that they think will win. And it makes it harder to put in a lot of work in time, if your hearts not in it. Some of the best projects, he adds, involve combining multiple interests.

Any advice for science fair newbies?

Staying on top of the news, Jacob says. Our middle school teacher showed us Science News and a couple of other websites that he just suggested reading every day, so that it got your brain thinking about: What do we know in science? And what dont we know? And then, finding the middle ground of what we do know and what we dont know to create your own project.

Rimoldi Ibanez competed in ISEF in 2018, 2019 and 2021. Her first projects investigated materials to limit radiation given off by smartphones. She then started studying how corals communicate through sound waves. Rimoldi Ibanez is currently a freshman at Florida Atlantic University in Jupiter.

What challenges did you face in your project?

When she first started studying corals, Rimoldi Ibanez tried growing them at home. Its the hardest thing ever! she says. I dont recommend it. For one thing, the corals were very sensitive. Also, creating a realistic ecosystem required filling the tank with fish, crabs and other creatures. The crabs and the shrimp just went after every single fish, she says. But the bright side of that project was that I was able to see that there were some acoustical sounds being emitted from the corals. The next year, Rimoldi Ibanez studied sound waverelated genes in corals at a research lab.

What was most memorable about ISEF?

Becoming part of this community that is so welcoming and excited to get to know each other. Thats really, really cool, Rimoldi Ibanez says. I love a good dance party, and they do a really good job with the dance parties at ISEF.

How has ISEF impacted your life?

I was very shy, as a middle schooler and in elementary. Because, when I moved here from Argentina, I did not know English, Rimoldi Ibanez says. But presenting at science fairs helped Rimoldi Ibanez gain confidence in talking to strangers. At first, my face would get super red when theyd ask me a question, she says. But later I realized, well, hey. Im the one who did all this work. I know all this information. Wanting to enjoy the social events at ISEF pushed her to be more outgoing, too. If youre shy and standing back, she says, youre not gonna get the same out of those events as someone who might be more confident.

In 2016, Toro Vega competed in ISEF with a project that simulated radioactive decay. In 2017, he returned as part of a team that built a hydroelectric energy generator. Today, hes a product manager at Apple in San Francisco, Calif.

What is it like working on a team, versus doing a solo project?

Working by yourself, you have the whole independence of leading a project, Toro Vega says. In a team, you have the opportunity to skill-share, divide the work. Teamwork is also good prep for working in the real world, he says. As a team, you actually learn how to communicate, manage deadlines, expectations between one another and at the same time, learn from each other. Plus, Toro Vega adds, joining forces with a friend can make doing a project more fun.

How has ISEF impacted your life?

I didnt really know what I wanted to study [in college], Toro Vega says. I knew I wanted to study STEM [science, technology, engineering and math], but going to ISEF and just walking around the computer science projects was like, I want to do this in the future. Having high-school research experience was also a huge bonus for college applications, he says.

Any advice for science fair newbies?

Just go for it, Toro Vega says. It might seem like its a huge road ahead. But the first step, the hardest step, is just starting. If youre unsure what topic to study, pick a few things that interest you and read about them online, he says. See if theres an issue that really calls out to you. And dont be afraid of failure, Toro Vega adds. Science isnt all about solutions that work. There are solutions that dont work, and from that we actually learn.

Wagner competed in ISEF from 2015 to 2017. She studied how to improve sporting helmets using inspiration from a woodpeckers head. Wagner now teaches high school chemistry in Saginaw, Mich.

What challenges did you face in your project?

Every step in science fair will give you a different problem to solve, Wagner says. For instance, I tested my helmets using a testing rig that Virginia Tech designed based off of real player data, and I replicated it in my garage. It was, like, 12 feet tall, built by hand myself. That took about three months, Wagner says. And you dont really get a lot of credit for all the hard work that you put into a project, not even the data you want to talk about.

Any advice for science fair newbies?

Any question that you can come up with about the world, in general, can become a science fair project, Wagner says. Keep asking questions. Be curious. And do it with a friend, if you really are discouraged about doing a project.

How would you describe ISEF?

I know a lot of people call it the Olympics of science fair, but it really is, Wagner says. And if youre a math nerd and you do the probability of making it to the Olympics versus making it to science fair, its actually harder to make it to ISEF.

What was most memorable about ISEF?

When you first arrive to ISEF, you meet students that are just like you, and you realize that youre not alone, Wagner says. You now have friends across the entire globe that are participating in a similar experience. And obviously winnings really nice and amazing and is an indescribable feeling. But the true prize is the experience itself.

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What it's like to compete in the science fair 'Olympics' - Science News for Students