Expert: ‘Our Understanding of Homologous Recombination Deficiency Is Evolving’ in Oncology Pharmacy Field

Pharmacy Times interviewed Christine Walko, PharmD, BCOP, FCCP, on her upcoming presentation at the 2022 Advanced Topics for Oncology Pharmacy Professionals (ATOPP) Summit on new developments for PARP inhibitors in homologous recombination deficiency.

Question: What is the prognostic and predictive role of homologous recombination deficiency for patients with cancer?

Christine Walko: I think our understanding of homologous recombination deficiency is definitely evolving. Traditionally, we thought of it as the BRCA1/BRCA2 mutations, and now we know there certainly are a whole lot of other genes that help with different types of homologous recombination repair that are important and that I will certainly be talking about in my presentation. But I think, in terms of the predictive role, traditionally, the presence of these alterations has been more likely to predict response to PARP inhibitors as well as a platinum-based therapy. Ovarian cancer, being one of our very classic diseases where we see this a lot, we know those patients often get adjuvant, neoadjuvant platinum-based therapy, and then in the maintenance setting, PARP inhibitors, which also have roles in the later line setting if they didn't receive it in the maintenance setting. The presence of these alterations either the BRCA1 BRCA2 germline somatic alterations, and/or the high HRD score, or even loss of heterozygosity, which is a piece of that HRD score, do suggest a higher benefit to the PARP inhibitors.

In terms of other disease states, I think we're still learning where that HRD score, the LOH score, loss of heterozygosity, homologous recombination deficiency will play. The majority of work has been in the ovarian space. However, there are some other investigations. There was actually a publication in JCO Precision Oncology that looked across different tumor types and did find that actually the most important aspect of predicting response to PARP inhibitors and platinum-based therapy is not just the presence of a single gene alteration in a pathogenic gene alteration, in BRCA1 or BRCA2, but rather that you have to have a biallelic loss. Both copies somehow, be it gene mutation, methylation large deletion, have to be inactivated, in order to see that. It is my hope that these homologous recombination deficiency (HRD) tests will hopefully continue to get better and better and really give us more the phenotype of the tumor that will allow us to prognosticate or predict better who are going to respond to these agents.

In terms of prognosis, we don't have as much data there that basically we know that cases with a loss of heterozygosity—if you have a loss of heterozygosity, you are more likely to have a better overall survival than a non-HRD tumor when treated with a DNA damaging agent. However, those tumors that had the loss of heterozygosity, HRD deficient—homologous recombination deficiency, who were not treated with the DNA damaging agents did worse than the tumors that did not have that LOH HRD score. It does seem like it may be a more aggressive phenotype, but again, there are some cancer-specific considerations that need to be taken into play and a lot of other just disease-specific patient characteristics in terms of the prognostic aspect of it.

Question: What are some new developments for PARP inhibitors in the homologous recombination deficiency treatment space?

Christine Walko: I think the biggest thing that I am the most excited about is the HRD scores themself. We are early on with this process. We have 1 companion diagnostic. Myriad Genetics does have the official HRD score, which is a companion diagnostic for olaparib and bevacizumab in the maintenance setting for ovarian cancer, and then also for niraparib, depending on how you say it, in the later line settings there. So, if you have a high HRD score and/or the presence of a pathogenic BRCA1 or BRCA2 alteration, your chance of responding is higher, and therefore you would qualify as the on-label indication for those 2 drugs in that space.

Obviously, in prostate cancer and pancreatic cancer and breast cancer the role of the PARP inhibitors is continuing to expand. The approvals are very different in these different cancer types. I think if you contrast prostate cancer, where the PROfound trial actually looked at a bunch of different mutations and patients that had a pathogenic alteration in 1 of many different genes involved in homologous recombination were enrolled in that trial. They did, in a subset analysis, kind of break down the outcomes based on the different genes with BRCA2 showing perhaps the best benefit. ATM, unfortunately, did not show as great of benefits, and there’s a lot of rationale as to why. But there seem to be differences between the effects of these different genes and the response to PARP inhibitors.

Again, going back to that finding, and I think it’s 1 of the most important things to consider about who is going to respond to PARP inhibitors, is if you have that biallelic inactivation. We don’t—outside of the HRD score, the loss of heterozygosity LOH score—they’re not the most ideal tests yet. Hopefully, we will continue as technology evolves to have better predictive tools to really discern who is going to respond and who is not. Hopefully, the approvals that we have may tighten down to really once we identify those populations that are most likely to respond.

Question: What are some emerging future technologies that could identify better predictors of response to PARP inhibitors?

Christine Walko: I think that's kind of what we were talking about already with the HRD scores and the loss of heterozygosity. Just a reminder that HRD homologous recombination score is 1 genetic company’s kind of secret sauce. They created this HRD score based on a combination of looking at chromosomal instability, so looking at telomeric allelic imbalances—TAI is the abbreviation for that—large state transition, so LST, and then the loss of heterozygosity, LOH. Those 3 things together make up what they calculate to be the HRD score, and then that was then validated and utilized in a prospective clinical trial that I will actually highlight as part of the presentation.

I think that the birth of that is certainly exciting. I also think just newer drugs as well that I alluded to: that ATM alterations, unless they're biallelic, even when they are biallelic, may not respond best to PARP inhibitors. However, we're looking at ATR inhibitors in that patient setting, and we do have some early phase data to suggest benefits there. I think our knowledge kind of starts small, and then we learn more, and technology allows us to grow and grow and grow and grow. We are in a growth phase and looking at where things are going to go in the future, but still having to treat the patients in front of us right now with the information that we currently have. Weighing risk and benefit with some of these less clear scenarios, I think is the clinical challenge with it.

Question: Are there any other novel agents in this pathway you plan to address during your session at ATOPP?

Christine Walko: My discussion is actually not as focused on the novel agents. It's more looking at the novel ways that the genetics may actually be represented to guide to the alterations that we currently have, and highlighting some of the clinical trials that are ongoing. My work in precision medicine involves looking at both tumor genetic testing and in cell-free DNA testing. For each of the kinds of stories and topics that I’m going to go to in this presentation, I have an accompanying patient case with the genetics. Doing a deeper dive into the BRCA1 BRCA 2, reminding everyone that it's not just the gene that matters, it's actually the mutation that matters too—we’re going to go through that a little bit. Then, also looking at some of the other genes that are involved in the homologous recombination pathway and what data exists to help support whether or not we would utilize a PARP inhibitor off label for a patient with a pancreatic cancer harboring a PALB2 mutation. We’ll talk about that. Of course, with ovarian cancer, we will go into the HRD, LOH discussion that I’ve already been kind of mentioning.

Question: What is the Oncology Pharmacy Book Group on Facebook, and why did you and Karen Fancher create it?

Christine Walko: This is definitely a fun question, one I love talking about. You can see my bookshelf full of many of the books that we have actually mentioned on there or that I got because they were mentioned on there. It started when—both Karen and I are part of the ACCP BCOP recertification course. Every year, we would always, as we’re between sessions or a dinner or whatever, start talking about different books that we were reading. We're both pharmacy nerds. My mom is a librarian, so I always have my stack of books to read. I can't remember what book it really started with, but I think she may have mentioned 1 specific book about the evolution of CLL—or CML—when she was giving her chronic leukemias BCOP presentation, and I wrote it down. I'm like, “oh, I need to check that out.” So, I got that book, and then of course, Amazon gives you, “hey, you should also check out these other ones.” We all just kind of organically started talking about it at those meetings.

Then she started the Facebook page where other people could write in and give recommendations. It's kind of grown. I think a lot of us really enjoy reading just books about the history of medicine. I think Emperor of All Maladies, obviously, touched a lot of us in that in the cancer realm, and just some of the other ones related to it. But it's just been a really—I love getting book recommendations, and there are so many good ones out there. It became a way to share that information and get other peoples’ opinions, but also just to collect, kind of do, I'm gonna say, a virtual book club. We have actually talked about trying to do that, in the future at one of the BCOP meetings or something.

But just getting different opinions, especially within our heterogeneous field of oncology and pharmacy, has just been something that's really enjoyable and kind of connects you to a whole bunch of other people, too.

Question: What are you looking forward to at the ATOPP summit this year?

Christine Walko: Physically being in person, I think immediately comes to the top. It will be really nice to, I think just network with people. You have a lot of different diverse topics that kind of span from real-cell novel therapies, putting things into practice, as well as some that are more operational. I think I'm always excited to—I always like the new practice updates, because things keep changing so much that it's hard to keep up. I'm also, kind of from a personal side of things, looking forward to seeing my mentor Howard McLeod, who is your keynote speaker. That will be a lot of fun as well.