Strategies Emerging for PARP Inhibitor Resistance in Ovarian Cancer

Kathleen N. Moore, MD

Although the addition of three FDA-approved PARP inhibitors has been game-changing to ovarian cancer treatment, a multitude of unanswered questions remain regarding whether patients can be rechallenged with a PARP inhibitor upon resistance, explained Kathleen Moore, MD.

“The questions we have to answer are several,” said Moore, the director of the Oklahoma TSET Phase I Program, and associate professor of the Section of Gynecologic Oncology at Stephenson Cancer Center, University of Oklahoma. “Does exposure to PARP inhibitors equate to resistance to PARP inhibitors? Are you ‘one and done’ with a PARP inhibitor or can you reuse it? How do you tell? If a patient progresses on a PARP inhibitor are they, by definition, resistant and [therefore] you would never reuse a PARP inhibitor, or are there ways to overcome that resistance?”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Moore combed through the various investigational strategies exploring management of resistance to PARP inhibitors in ovarian cancer.

OncLive: What is the state of managing PARP inhibitor resistance in ovarian cancer?

Moore: Less than 1 year ago, we saw the approval of olaparib (Lynparza) for maintenance following frontline chemotherapy in women with BRCA-associated advanced ovarian cancer. That is a very exciting development that will hopefully convert many of those women into long-term, disease-free survivors.

But, unfortunately, some of them will recur and will need additional therapies. Therefore, the questions for them that will come up relatively soon in the next few years are, “What’s next? Do you reuse PARP inhibitors in these patients? Are they resistant to PARP inhibitors? How do you assess for that, [and how do you know] what the next best line of therapy is for that group of women?”

Of broader importance is the fact that we know now, through a press release, [about] the PRIMA study. This is also a frontline ovarian cancer study in a broader population; it is inclusive of women with BRCA-mutant cancers, but also BRCA wild-type cancers. [The patients] were randomized to niraparib (Zejula) maintenance versus placebo maintenance following response to frontline chemotherapy, which is very similar to the SOLO-1 trial.

While we don’t know the details of that study, we do know via a press release that it is a positive trial. Therefore, we can potentially anticipate a new indication in a broader population of women. In addition to that, there are 2 large phase III studies that are evaluating the use of a PARP inhibitor following response to frontline chemotherapy in a population beyond BRCA-associated cancers. We don’t know those results yet, but we are anticipating them this year. It is entirely probable that the standard of care for women following response to frontline chemotherapy will include a PARP inhibitor. That may be in all-comers, or it may be in molecular subtypes beyond BRCA mutations, but, undoubtedly, the indication for PARP inhibitors is going to expand.

We already have a very broad indication in the platinum-sensitive recurrent setting where all-comers, regardless of BRCA mutation status, can access the maintenance PARP inhibitors rucaparib (Rubraca), niraparib, or olaparib following response to platinum-based chemotherapy in the recurrent setting. We have an increasing number of women who have been exposed to a PARP inhibitor; until SOLO-1, all of those women were treated in the recurrent setting and were usually treated until recurrence—not always, but usually.

Therefore, this question of reuse of PARP inhibitors was sort of out there, but it wasn’t as urgent of a question. This is because the indication for PARP inhibitors in the recurrent setting is platinum-sensitive recurrent maintenance, or in the third-line and beyond setting if you have a BRCA mutation. [Reusing a PARP inhibitor] wasn’t really indicated but it was something people wondered.

Now that [this class of drugs] is going to be [used as] frontline maintenance, you’re going to have women receiving [treatment over] a specified number of months during a time we hope they don’t recur. They are going to discontinue use of a PARP inhibitor and then hopefully not recur, but some of them will recur during treatment or some [may recur a] number of months or years later.

There are other patients who, even though they may have BRCA mutations or other clinical biomarkers that would indicate that they may benefit [from PARP inhibitors], they are for whatever reason, never going to benefit. Are there tests we can do? Are there biomarkers we can develop? That will really help us sequence which therapy is the right therapy. Those questions are coming now. Our patients are going to be expecting clinical trials to be available and [we need to] be mobilizing our best scientists to evaluate how to maintain sensitivity to PARP inhibitors, so that we can continue to provide sequenced therapies to women over their lifespan.

What we know in the United States and in Europe is that the development of active therapies in the recurrent setting has resulted in this increased prevalence of women with ovarian cancer. Even though we have no decrease in incidence, and unfortunately no decrease in mortality, we have more women right now living with ovarian cancer than we ever had is our history. Why is that? [It is] because they are living longer. We have these active, sequenced therapies.

Now that we are using some of our best sequenced therapies earlier on, we’re going to have to be developing these clinical trials that will help us identify how to triage women when they recur to the next best line of therapy. Now, whether that includes a PARP inhibitor, or maybe we never use a PARP inhibitor, we need to have those answers. We can’t continue to be empiric; that’s not good enough. We have the science that will help us to, in some settings, identify patients for whom PARP inhibition is a good idea and for whom it is not going to work in.

Are there trials underway or anecdotal reports of repeat exposure to PARP inhibitors?

There are anecdotal reports; they are very new. There have been 2 very small, retrospective analyses. One was a multicenter, retrospective study of 5 sites that found anyone who had been given a PARP inhibitor more than once. Kathleen Essel, MD, was the lead author; these are small numbers, but what she found was that there were responses to repeat PARP inhibitor use. However, all of those patients had been exposed to a prior PARP inhibitor and had not progressed on one; and all of the patients who responded had a BRCA mutation. This doesn’t necessarily say anything about who should get a PARP inhibitor other than that we did see some responses, so there may be a signal there.

The QUADRA study was a prospective, single-arm phase II study of niraparib in a broader population of heavily pretreated patients with BRCA-mutant associated cancers, but [included] many more non-BRCA—mutant associated cancers. It did allow a history of PARP inhibitor use, so it didn’t exclude the patients from going on the study. [There were approximately 30 women] who had prior exposure to PARP inhibitors, and they had progressed. [Results showed] relatively the same thing; there were fewer responses, but there was some clinical benefit and no safety signals in either study.

It is too small to make any big deal of at this point, but the ongoing clinical trial—the big one—is the OReO study. It has been going on for a while; it’s picking up steam with the approval of olaparib as frontline maintenance therapy. It has become a much more important study. It takes women who have platinum-sensitive recurrent disease, both BRCA- and non-BRCA—mutant associated cancers, and had prior exposure to PARP inhibitors and then they had to respond again to chemotherapy. Then, they were randomized to olaparib or placebo. Therefore, it is a pure PARP inhibitor maintenance or placebo maintenance question in patients who had seen prior PARP inhibitors.

Another study is the EVOLVE study; Stephanie Lheureux, MD, and her colleagues took women who had progressed on a prior PARP inhibitors, and then explored one of the reported mechanisms of acquired resistance to PARP. One of the ways that you develop resistance to PARP inhibitors is you upregulate a pathway that restores homologous recombination proficiency (HRP) by a number of mechanisms. One of those pathways is VEGF, so if that is upregulated through downstream events, you can restore HRP, or the cell's ability to fix itself. If it can fix itself again, it won’t be responsive to PARP.

Therefore, there is a theory that you can combine PARP inhibitors with antiangiogenesis, such as bevacizumab (Avastin) or the TKI cediranib to try and overcome that acquired resistance. This was a very small, translational science—driven study, and they looked at mechanisms of escape in platinum-sensitive, platinum-resistant, and unknown patients. There were [about] 10 in each cohort; there were some responses. They were low numbers—maybe 2 in each of the 3 groups had responded—but again, this is a very small study so it is hard to make efficacy statements from it. [Further data] will be very important information for us to build on as we design this next phase of trials. That is one of the more completed prospective trials that launches us into this next phase of drug discovery.

Does the PI3K pathway have any role in overcoming resistance to PARP inhibitors?

The pathways that can restore HRP are VEGF, PI3K, ERK, and BET; there is some suggestion that androgen receptor upregulation has a role there, and maybe more than one is in play. One [pathway] is responsible for the main aspects of HRP, so we have quite a bit to learn. With PI3K, we do have data and they are very early.

Panagiotis Konstantinopoulos, MD, PhD, has done the most preclinical work of the synergy between a PI3K inhibitor and olaparib, and he has done phase I work demonstrating that the dose that can be combined and [the combination has] efficacy among patients with BRCA-associated recurrent disease—there was a group of patients who had prior exposure to a PARP inhibitor as well. Therefore, it wasn’t just a study in PARP inhibitor—resistant patients, it showed that we can combine these drugs [and] hopefully disrupts that restoration of HRP. That has been proposed as a randomized phase II study and we are hopeful that it will develop into a bigger trial where we can evaluate whether that combination versus physician’s choice of chemotherapy in a variety of settings will be beneficial to patients [who are resistant to PARP inhibitors]. That has not been solidified, but it is under development by researchers at Dana-Farber Cancer Institute. There has been some other work combining AKT inhibitors and PARP inhibitors, and the BET combinations…are very exciting but are too early to comment on.

Since some of these studies are not yet widely available, what do you do currently when one of your patients develops resistance to a PARP inhibitor?

If you have a patient who received a frontline PARP inhibitor, didn’t progress on it, and then recurs who knows how long later, the best clinical predictor is still platinum-sensitivity. If I have a patient who re-responded to platinum-based therapy, I might try PARP inhibition as maintenance treatment again. Hopefully, we will develop the ability to screen for mechanisms of resistance.

There are data out of ARIEL2 that look at circulating tumor DNA, which identified BRCA reversion mutations. If [these reversion mutations] were identified in this blood test, they did not respond [to rucaparib]. These are patients who are PARP inhibitor—naïve, but they previously received platinum-based therapy. [A patient could] have the BRCA mutation, but for some reason the protein is being transcribed normally again, so it could be a reversion mutation or epigenetic changes that basically restore normal BRCA protein levels—basically, the patient [does not have a BRCA mutation] anymore.

If you can determine that upfront [from a blood test], and you know it predicts lack of response to PARP inhibition, then it would be informative in that group of patients as to whether or not you would put them on a PARP inhibitor, a clinical trial with an alternative agent, or bevacizumab, which is a great option for maintenance in patients and has an overall survival advantage. We are not there yet commercially, so it’s not something [where I can say], “Oh, I’m going to test for that.”

Is there anything else you would like to add?

Ovarian cancer is a cancer of homologous recombination deficiency and a large percentage [of cases] are high-grade and serous. PARP inhibitors have been game changing, but there are other DNA damage-response agents that are in the pipeline. WEE1 inhibitors, ATR inhibitors, CHEK1/2 inhibitors, and a number of combinations that act in pathways other than PARP may not work or may be great. Those may be things we go to next; this idea of capitalizing on the inherent vulnerability of ovarian cancer, in terms of how it fixes its DNA, is going to continue to be a critical player for us in developing new assets either as monotherapies or in combination. Those are all kinds of new assets moving into the phase II setting, so we have a way to go next to figure out what their potential is.