Expanding the Role of PARP Inhibitors: Emerging Strategies in BRCA+ and HRD+ Breast Cancer

In this episode, Dr. William Gradishar reviews key data on PARP inhibitors in breast cancer, including early insights from the OPERETTA and CompLEEment trials. He explores emerging combination strategies with immunotherapy and DNA-damaging agents, the potential to reduce chemotherapy use, and new tools to better identify candidates for targeted treatment.

Transcript

Dr. Gradishar: Hello, I’m Bill Gradishar, Professor of Medicine. I’m the faculty at Northwestern University in the Robert H. Lurie Comprehensive Cancer Center. And I’m pleased to discuss some of the abstracts and presentations from ASCO this year that focused on PARP inhibitors.

And PARP inhibitors, I think, as everyone knows at this point, otherwise known as polyadenosine diphosphate ADP-ribose polymerase inhibitors, that’s why they call them PARP inhibitors; it’s easier to say, have been shown to be useful in patients that harbor BRCA1 and 2 mutations, both in the early stage and late stage setting.

In the late stage setting, we have two drugs that are approved: talazoparib and olaparib. And they’ve shown to be effective with fewer side effects than what chemo monotherapy can provide to patients with metastatic disease who have BRCA1 and 2 mutations. So these drugs become viable options as an alternative to chemotherapy.

And then, in the adjuvant setting, we’ve had the approval of olaparib based on the OlympiA trial in patients who are at high risk of recurrence. And again, if you meet the criteria, having sufficiently high risk following standard chemotherapy, a PARP inhibitor would be a consideration for a year.

And again, these data have been out there for a while, and we know that these drugs have been useful and have been beneficial to patients. But, of course, we’re trying to understand how they might be optimized even with other drugs or in other settings.

So that really lends itself to thinking about how we use these drugs in sequence with all the drugs that are now being developed: antibody drug conjugates, immunotherapy often used with chemotherapy, and consideration based on preclinical data would suggest that combining PARP inhibitors with any of these newer agents may offer some benefits because of a unique mechanism of action that may exploit not only what PARP does, but what the other targeted agents do.

And they may have more synergy together than they would as an individual agent.

So, to that end, there were a couple of trials that were highlighted more or less based on preclinical data because we don’t have a lot of data from the trials themselves.

The OPERETTA trial, which is a phase two study evaluating neoadjuvant and adjuvant olaparib plus pembrolizumab following platinum-based chemotherapy plus pembrolizumab for patients with germline BRCA mutated triple negative breast cancer.

And this is an ongoing trial. Men or women who are 18 years or above can participate. They have to have triple negative breast cancer as well as a confirmed germline, BRCA1 and 2 mutation, and they have to have non-metastatic disease.

And they receive preoperative standard chemotherapy with the taxane, carboplatin, and pembro. And that after four cycles, chemotherapy is discontinued, and rather than chemotherapy, olaparib is added to the pembrolizumab again for about 12 weeks.

And then the patients go to surgery after which they continue on olaparib and pembro postoperatively for nine additional cycles.

And again, the rationale for this is because there has been demonstrated synergy between immunotherapy and PARP inhibitors preclinically, and this would be an effort to see if you could avoid giving as much chemotherapy and possibly gain greater benefit as judged by not only pathologic complete response rate, but ultimately for a longer overall time without disease recurrence.

The other trial taking a somewhat different tack that, again, is currently underway, we don’t have, again, a lot of data, but we have preclinical data that would suggest that this might be a reasonable approach, is combining olaparib with a compound called ASTX727.

And this is a drug that is basically synergistic with trapping and causing more DNA damage, a HiDAC compound.

And again, the poster that was presented at ASCO by Pam Munster and her colleagues from UCSF really focused on some of the preclinical data that supported the synergy between these two drugs, demonstrating that you were getting more of an effect by using both of these drugs than either one alone.

And in this case, the PARP inhibitor that was used was talazoparib in the preclinical models. In the clinical trials, looking at rather than talazoparib, looking at olaparib plus ASTX727.

So first starting out in advanced solid tumors, not necessarily breast cancer alone.

And then there’ll be a so-called combo match phase two trial where, again, not only tumors of different types, but a cohort that has breast cancer as well as specific mutation types that include things beyond BRCA1 and 2.

So we don’t have data from these trials, but it really gives a lens on where the field is going.

And I think it’s not surprising because if you think of a topic we’re not talking about, endocrine therapy, even though we have a number of new drugs that are in development, where a lot of the focus is, is how can we combine these with other drugs to optimize and maximize their benefit?

And that too is being done in the setting of PARP inhibitors, trying to understand if by combining them with other compounds, immunotherapy, HiDAC inhibitors, or other drugs, we might be able to exploit their unique mechanism of action and get a better effect both in early and late stage disease.

So again, there’s a lot of work going on, and one of the challenges that we have is trying to figure out who are the candidates for immunotherapy. And there was an experience that was reported from Israel looking at a unique platform that really looks at PD-L1 expression, which is one of the biomarkers that we typically use to try and understand who is a candidate for immunotherapy. It’s the one and best biomarker we have, certainly in the metastatic disease setting.

In the preoperative setting, where patients have earlier-stage disease, we’re sort of agnostic. If you have triple-negative disease to the PD-L1 status, then a patient is eligible for pembrolizumab. But in the metastatic disease setting, we really look for expression of PD-L1, and if it is present at a high enough level, then we would consider pembrolizumab as a treatment choice.

So what this platform is referred to is as DEEP-PT. And what this experience, in admittedly, a small number of patients was, was looking at 19 patients with metastatic triple-negative disease who were treated with olaparib and durvalumab, an immunotherapy checkpoint inhibitor. And they were evaluated in a more typical way based on IHC for PD-L1 status. And the classification was determined as positive if they were greater than 10% or 25%, depending on the monoclonal antibody that was used.

In addition, they looked at the same samples with the DEEP-PT platform to infer the whole transcriptome, and specifically looking for PD-L1 expression from the H&E slides. So again, it’s basically another extension of looking at what AI might be able to help us with as a pathology tool.

And what they were able to determine from that report, again, a small number of patients, but it was pretty intriguing, and that was that the DEEP-PT platform was highly predictive, with an 80 to 90% positive predictive value and an 80% sensitivity for PD-L1 expression. And this was much better than what you could get with the typical IHC that we use in most pathology labs.

So this speaks to the effort that we all have on trying to be more selective in identifying patients who are candidates for specific drugs. And this may be a tool, not yet ready for prime time, but a tool that we may be able to look to in the future for more selectively identifying patients and/or tumors that would benefit from immunotherapy. So we’ll have to stand by and see what else we hear from that as well.

There was also a trial that was presented, it was one of the oral presentations that I think is worth mentioning, that’s the ABCSG-45 trial. And this was a prospective trial that was presented on behalf of the Austrian Breast & Colorectal Cancer Group. And it basically looked at a randomized phase two study of carboplatin-olaparib in preoperative treatment of patients with triple-negative primary breast cancer who exhibit features of positive homologous recombination deficiency, or HRD positive status.

And we’ve known for some time that about 50% of patients who have HRD-positive triple-negative breast cancer also harbor pathologic variants of BRCA1 and 2. So it’s a subset of those patients. And we also know that when we go through this, that chemotherapy with platinum-based drugs is effective in this population.

So what this study did was identify a group of patients like this, triple-negative breast cancer, HRD-positive, randomized one-to-one, again a randomized phase two trial, to either get six cycles of carboplatin-olaparib or six cycles of TAC: taxotere, anthracycline, as well as cyclophosphamide. And then this was all administered preoperatively. Patients went to surgery.

So there were 90 patients that were randomized. And the primary endpoint was to look at what were the fraction of patients who had a pCR, as well as looking at residual cancer burden, as well as the tolerability, quality of life, et cetera.

So the key points for inclusion, I’ve already mentioned, you had to have at least a T1C lesion. Any nodal status was allowed, but you had to have HRD-positive status, meaning the tumor was either BRCA1 or 2 pathologic variant or a genomic instability score of greater than 42.

And if you look at the data from the trial, basically what it demonstrated was that the patients who had HRD-positive triple-negative breast cancer were clearly sensitive to an anthracycline/taxane-based regimen. Patients who had BRCA1/2 pathologic variant had a very high rate of RCB scores of zero or very minimal residual disease, 77%.

And the main toxicities with that combination of carbo and olaparib were primarily hematologic: thrombocytopenia and neutropenia. And the TAC arm, which has been around for a long time, really didn’t show anything that we were unaware of before.

So the point of this was that we might be able to identify patients who, based on their BRCA1/2 status, HRD-positive status, could be candidates primarily for a non-chemotherapy preoperative regimen. Because in the patients who had a BRCA1/2 status, where they were mutant, had a 77% RCB score of zero, without chemotherapy.

So this, again, speaks to being more selective with therapy. Is this ready for prime time yet? No. But it’s intriguing and may offer new directions for how we think about these patients going forward.

Another interesting study that was presented in preliminary fashion was the COMPLEMENT study. And this was a trial that looked at induction platinum-Abraxane-pembrolizumab, followed by pembrolizumab with or without olaparib maintenance in triple-negative breast cancer was a randomized phase two trial. The results are not yet completely mature; it’s not completely accrued. But it’s interesting because the way this trial was set up is patients who had completed all their primary therapy and then developed recurrence were potentially eligible for the trial. And that included some patients who may not have been viewed as triple-negative when originally diagnosed, but at recurrence were determined to be triple-negative.

And how the trial was designed was in the eligible patients who at recurrence had metastatic triple-negative breast cancer with a PD-L1 CPS score greater than one, and they had to have an interval between the completion of their curative intent treatment of at least six months, getting no active steroids, no active CNS disease. Received platinum-nab-paclitaxel plus pembrolizumab for four to six cycles, and then, if they had anything other than progressive disease, so a CR, PR, or stable disease, were then randomized to receive pembrolizumab alone or pembrolizumab plus olaparib.

And again, the way the patients were stratified was based on their clinical response, their genomic tumor status, whether they are BRCA mutant or wild type, and whether they had visceral metastasis or not. And the trial was designed for a total of 132 patients. When this was reported right before it went to San Antonio last year, there were 52 patients enrolled. And the majority of them did have triple-negative diagnosis at the outset, meaning right when they were first diagnosed. But there were a handful of patients, about 11, who converted, they were originally not triple-negative, but then at evidence of metastatic disease, rebiopsy showed that they were triple-negative.

And the response to the induction treatment was quite high. So again, this was platinum-Abraxane and pembrolizumab, and it was 86%. And the time to response was also quite rapid, a month and a half. So at this point, once patients were determined to have a response or stable disease, they either went on to pembro or pembro plus olaparib. And again, we’re starting to get into small numbers, there were roughly 15 in each group. And the medium progression-free survival was not achieved yet in both groups. At this point, what they can say is that they’re pretty similar. The pembro-olaparib is about 11 months, and the monotherapy pembro arm is about nine months.

So we don’t have long follow-up, but one thing that was an interesting observation is that the patients who had originally been something other than triple-negative but were triple-negative at recurrence seemed to benefit less from this strategy, so their PFS was six months versus those that were triple-negative from the get-go, where it was about 12 months.

So again, what this trial is trying to get at, is there an optimal maintenance strategy that you can employ after you discontinue chemotherapy? Should something be added to pembrolizumab in these patients, and might that be olaparib? And this is one strategy that’s being explored. We only have preliminary data. I think it’s of interest, but we’ll need to see the full data set before we get an understanding of whether this is something that should go forward into a larger trial.