Role of PARP Inhibition Shifts in Ovarian Cancer as Research Efforts Expand

Robert L. Coleman, MD, FACOG, FACS

With 3 PARP inhibitors approved by the FDA for use as frontline maintenance in patients with BRCA1/2-mutated ovarian cancer as well as in the recurrent setting, researchers continue to evaluate the role of this class of drugs in the treatment paradigm and how their use may be expanded, according to Robert L. Coleman, MD, FACOG, FACS.

One such inhibitor, rucaparib (Rubraca), received approval in April 2018 as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy based on data from the phase III ARIEL3. Median progression-free survival (PFS) was 10.8 months with rucaparib versus 5.4 months with placebo. The overall response rate with rucaparib was 18%. In those with either germline or somatic BRCA mutations, a 77% reduction in the risk of progression or death was reported with rucaparib compared with placebo (HR, 0.23; 95% CI, 0.16-0.34; P <.0001).

Many of the toxicities observed with the agent are similar to those observed with the other 2 FDA-approved PARP inhibitors: olaparib (Lynparza) and niraparib (Zejula). The most common associated toxicities observed with the agent are gastrointestinal (GI) events as well as fatigue, according to Coleman. However, the hematologic toxicities observed with rucaparib may slightly differ from what is seen with the other PARP inhibitors, Coleman added. Rucaparib is now being examined in combination with other agents in ongoing trials.

“Rucaparib was 1 of these 3 PARP inhibitors that has a similar effect in respect to inhibition of the catalytic activity of PARP,” said Coleman, a professor and Ann Rife Cox Chair in Gynecology, in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center. “The agent was initially studied in patients who carried a BRCA mutation, as well as those who had a vulnerability identified via a loss of heterozygosity test.”

Clinical trials are now evaluating the potential combination of PARP inhibitors with immunotherapy or other agents in patients with ovarian cancer. In particular, investigators are combining PARP inhibitors with immune checkpoint inhibitors in the frontline setting. Although the population of PARP inhibitor—naïve patients is becoming smaller over time as more of these inhibitors are used in the frontline setting, the hunt to find a combination regimen that would provide these patients with more benefit than that of single-agent PARP inhibition continues.

In an interview with OncLive during the 2020 SGO Winter Meeting, Coleman discussed the role of rucaparib as a treatment option for patients with ovarian cancer, how this agent compares with other PARP inhibitors in this space, and where research is headed for these agents.

OncLive: How have PARP inhibitors evolved in ovarian cancer over the past few years?

Coleman: We have known for quite a long time now, almost 15 years, that cells that lack an intact homologous recombination pathway, best defined by a BRCA mutation, are exquisitely sensitive to PARP inhibitors. The hypothesis for the mechanism of action for these inhibitors [is that they] would prevent single-strand repair or they would be trapped on the DNA during the replication process and lead to these double-strand breaks, which would then tax the cell to come up with a mechanism to fix. Several mechanisms can be leveraged for repair on double-strand DNA breaks, the highest fidelity of which is homologous recombination; however, other pathways can lead to [error-]prone repair.

The concept was that if we gave this medication in tumor cells that lack this high fidelity repair mechanism, they would have this synthetic lethality leading to cell death. PARP [inhibitors alone] weren’t necessarily killing the cells, and the lack of an intact homologous recombination pathway in the cell would not necessarily kill it either; having the 2 together led to the heightened cell kill that we saw. With that in mind, we knew we could identify patients whose tumors carried a BRCA mutation. That is where the story started with the incorporation of PARP inhibitors into the clinical domain.

What are the data that support the use of rucaparib in ovarian cancer?

Rucaparib is 1 of about 5 PARP inhibitors now that are working their way through clinical development. Rucaparib, olaparib, and niraparib are 3 that all have FDA approvals. We expect those labels will be expanded even further this year.

A large phase II trial called ARIEL-2 was done with the intent of capping patients who had a BRCA mutation. The study was combined with another study referred to as Study 10, to examine the efficacy [of rucaparib] across multiple cohorts. What we essentially saw was that rucaparib produced responses in patients who not only had the BRCA mutation, but also those who carried an alteration identified by loss of heterozygosity. That was in patients who had actual disease that could be measured. [The agent] moved into the maintenance phase where patients who had observed response to platinum and recurrent ovarian cancer were randomized to receive either placebo or rucaparib. Results demonstrated an impact on PFS [with rucaparib] for all analytical cohorts, which included those with BRCA-mutant disease, those with homologous recombination deficiency, and the entire intent-to-treat population.

What are the toxicities associated with this particular PARP inhibitor?

Rucaparib, as I mentioned, is a PARP inhibitor that shares an essential number of class adverse events (AEs); they are predominantly GI and fatigue, but the hematologic toxicities might be slightly different than what is seen with the other 2 PARP inhibitors that have been studied in this setting. We see some transient elevations in creatinine, which we believe are related not so much to kidney injury as they are to creatinine transporters. This is not completely unique for rucaparib, but it is just something we noticed in the trial.

The other AE we saw was the transient elevation in liver function; this should be in the low range, but it was around 2 times what it should normally be. Also, we are seeing these events are essentially resolved on their own, and most of them appeared really early on. Furthermore, these events did not lead to any other medical problems. Many times, we were able to manage patients through these transient elevations without issue. The other effects we see on bone marrow, such as myelosuppression and anemia, are singular across the PARP inhibitors themselves, so it does appear to be a class effect that we observe with these drugs, not something with rucaparib alone.

How does rucaparib compare with the other PARP inhibitors?

The PARP inhibitors are all very similar. At least from an efficacy standpoint, it is very difficult to make a definitive statement about that because we have not done the trials that compare them directly. However, we see a similar effect across the different tumor types that we have addressed, such as the platinum-sensitive space, where the drugs indicated have shown very similar activity. The 3 PARP inhibitor trials carry have similar take-home messages. These agents are very [comparable] in terms of efficacy, but they can have slight differences in their safety profiles.

What are the next steps for PARP inhibitors in ovarian cancer?

The PARP inhibitors, as a class, are undergoing a massive revolution. We have already demonstrated that these drugs have single-agent activity; that is a given. They started in the recurrent/resistant space and have since moved to the frontline space where they are now being used. These agents are already approved for use as primary maintenance in patients who are biomarker-defined, and we expect that with the current trials that are being filed, the addition of veliparib will bring a fourth PARP inhibitor into this space for use as frontline treatment.

All of the work we have done with regard to recurrence will be more difficult to interpret mainly because we feel there will be a very substantial proportion of patients who have already been exposed to a PARP inhibitor. One of the first questions we will need addressed in the immediate future is, “What we are going to do with patients who have had prior exposure to a PARP?” How we can allocate these patients onto clinical trials that are addressing the efficacy of subsequent therapy? The short-term view of what I believe will happen next is, we will be looking at studies addressing the question of whether or not [previous exposure to] PARP inhibitors is important? In other words, do these patients progress? Do they have a PARP-free window? That is important to know. Is it one-and-done? Are you only able to use a PARP inhibitor one time?

Another ongoing strategy is evaluating whether or not we can restore the sensitivity of PARP if these patients have had prior exposure to these agents and have progressed on them. What do we do for PARP resistance? How do we augment the activity in the patient population? In the recurrent setting, is there an opportunity to take a biomarker-negative tumor, which we refer to as a homologous recombination—proficient tumor, and figure out a way to make PARP inhibitors a part of the story?

In 10 years, we will have maturing overall survival (OS) data with these drugs in studies that have already been done. Next, we will see data from the current crop of trials that will report on the combination of PARP inhibitors with immunotherapy, such as checkpoint inhibitors, and antiangiogenic drugs in the frontline setting. In the next 5 years or so, we will start to [learn more about] these combinations and [hopefully be able to] make primary efficacy decisions based on first, PFS and, ultimately in 10 years, OS. In the next decade, we will see expansion of

PARP combinations, and in the recurrent setting specifically, we will see expansion and development of PARP combinations for those who either have had previous exposure to these inhibitors or those who are PARP-naïve.

Is there anything else that you would like to add?

One of the most significant things that we will hopefully see in the next 10 years will be development of a real-time assay that will assess the continued, or lack of continued, vulnerability to this kind of class of drugs. What I mean is that I hope we will see an assay that is not based on tumor biopsy, one that will be able to tell us in the microenvironment or not whether the tumors have compliant or noncompliant homologous recombination. [With that information], we could make a decision either before treatment or, more importantly, during treatment, [and understand] whether or not these drugs will continue to work.

The elephant in the room here is the financial toxicity that these potential triplets or combinations will have to patients. It will be extremely expensive to run these trials in all-comers, so if we can identify the patients who would benefit the most [from these approaches] or identify those in whom the benefit is going to be lost, we would be able to provide a better overall stewardship on the use of these compounds as we continue to look at active agents for our patients.

Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: a phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC). Ann Oncol. 2017;28(suppl 5; abstr LBA40_PR). doi: 10.1093/annonc/mdx440.034.

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