Analyses from the phase III ARIEL3 trial presented during the 2019 Society of Gynecologic Oncology Annual Meeting showed that rucaparib is safe and effective as a maintenance therapy across all subgroups of patients.
Robert L. Coleman, MD
In findings from the phase III ARIEL3 trial, maintenance therapy with the PARP inhibitor rucaparib (Rubraca) demonstrated an improvement in progression-free survival (PFS) in patients with platinum-sensitive recurrent ovarian cancer. Further analyses presented during the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting showed that this therapy is safe and effective across all subgroups of patients, regardless of age.
Based on findings from the ARIEL3 trial, the FDA approved rucaparib tablets in April 2018 as a maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
During the SGO Annual Meeting, results were presented from 2 post-hoc exploratory analyses that investigated specific cohorts of patients in the randomized, placebo-controlled ARIEL3 trial. One analysis, presented by Robert L. Coleman, MD, looked at the efficacy and safety across several different subgroups of patients, including wild-type, somaticBRCA-positive, non-BRCA, loss of heterozygosity (LOH)-high, and LOH-low. Additionally, Jonathan A. Ledermann, MD, of University College London, presented results on the safety and efficacy outcomes with rucaparib across different age groups.
PFS seemed to significantly improve in all cohorts of patients. In addition, the safety and efficacy appeared similar across all age groups.
“I think we have confidence that in all of these clinical scenarios, there is a measured benefit with the use of these drugs,” said Coleman.
In an interview withTargeted Oncology,Coleman, professor in the Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, discussed the results from these 2 analyses presented at the meeting, as well as the role of PARP inhibitors across different settings for patients with ovarian cancer.
TARGETED ONCOLOGY:What are the main points that are important to understand right now in regard to PARP inhibitors in ovarian cancer?
Coleman:As you know, PARP inhibitors are a big important topic right now, especially now that we have developed them in the recurrent setting, first as treatment in multiply-treated patients, less heavily treated patients, secondary maintenance, and now as primary maintenance. There’s lots of work looking at the roles of these drugs in those settings, and it’s continuing to expand.
The good news is that we have a lot of great options. The down side is many of these patients ultimately recur, so we need to figure out what to do next. A lot of the work that’s going on now is looking at ways to either enhance, to overcome resistance, or to take a patient population that is wild-type and see if we can figure out a way to make them sensitive to these agents.
It’s really been quite exciting, and there’s a lot of work that’s been going on. Here at the meeting, we’ve seen a few presentations that are looking at essentially each of the PARP inhibitors in multiple different roles, both as a treatment and as a maintenance. We are learning how to dose them better, learning how to take proactive attempts as a better way than waiting for toxicity and then having to make adjustments. The good news is that the therapeutic index on these drugs is quite large, so what we are seeing from the several presentations here at the meeting is that even these dose modifications are not impacting the clinical efficacy in a negative way, but making it more tolerable. Those are really strong and important messages, especially as we start to look at ways to augment them by using them in combinations where we might expect to see more toxicities, so that’s been an important role for a lot of the new and current clinical investigation.
TARGETED ONCOLOGY:Could you discuss some of the background to the ARIEL3 trial?
Coleman:Since the publication of ARIEL3, we have learned quite a bit about the role of rucaparib in preventing progression in patients who have responded to platinum. There’s lots of nuances in all the trials, but in this trial itself, we learned that patients who have aBRCAmutation either known in the germline or known in the tumor only, as we would call it the somatic mutation, or they have this LOH, which is kind of a reflection of a DNA damage repair mechanism that’s not working properly, that in each of these subgroups of patients there was some benefit. Depending on how you group the patients, we are seeing pretty strong effects in all of these situations. Leading to the entire treatment population that came on the study, they had essentially a doubling of their median PFS, so it’s a very strong effect.
TARGETED ONCOLOGY:What were you looking for in your exploratory analysis of these data?
Coleman:What we decided to do in this paper was to look at [how] most patients don’t have tumor testing, so the somatic knowledge is just unknown. In this particular trial, we had this data that we could actually sort though. What we looked at in this trial was essentially the patients that just had germline because we know that most of the patients with ovarian cancer are now getting germline tested at a minimum. We just looked at that group and then what happened to the rest of the group. The rest of the group was truly wild-type, there were somatic patients in there, somaticBRCAmutation patients, and patients with high or low LOH. We just looked at germline versus non-germline, and what we shown was consistent with the primary outcome of this study, that there was a very, very strong effect in the hazard ratio between 0.2 and 0.3. This was a very, very strong effect.
We said that’s interesting, so let’s look at the group that was germline wild-type. Let’s start to look through that subgroup. As I mentioned there were multiple groups in there including truly wild-type, somaticBRCA-positive, LOH-high, and LOH-low. We said, okay, is this effect that’s seen in the germline wild-type population, is that due to these other things that we know that these drugs work? For example, somaticBRCA. What was shown is that yes, these things do define some of that outcome, but not all of it. Even in the patients that are completely wild-type by our best measure, so no LOH, no somaticBRCA, no germline, there’s still benefit. What it tells you is that our testing for being able to sort through and being able to tell where there is real DNA damage expression of the defect in that mechanism is just not as precise as we can be, but right now, I think we have confidence that in all of these clinical scenarios, there is a measured benefit with the use of these drugs.
TARGETED ONCOLOGY:Could you also discuss the exploratory analysis investigating the effect of age in the ARIEL3 trial?
Coleman:Another really interesting presentation that Dr. Ledermann did, which was also based on the ARIEL3 trial, was to look at the effect of age. If you think about it, the demographic of patients as they go onto a clinical trial, that’s one of those that you can’t really change. You can build your eligibility criteria about what is the age range you will take, but we do know that age is an important prognostic factor across the board. You just have less life expectancy as you get older. What we did in this trial was to look at whether or not there was any kind of age effect that we saw there, particularly not only on efficacy but on toxicity. We know that sometimes elderly patients have a much more difficult time with drug toxicities, and many of them have a lot of other concomitant medications that can make the drug-drug interactions more likely to happen. What was reassuring about the trial was that we found that the benefit we saw with rucaparib in all of the subgroups was similar to what we saw in the overall study. It seemed to be efficacious in all of these groups, and for the most part, the toxicities were really not all that different. Tolerable drug, no matter what the age. Efficacious, no matter what the age. One slight difference we saw is that there might be slightly more treatment discontinuations in that older population over age 65, but again, this provides real confidence that this drug has activity and a safety profile which is pretty robust and seems consistent across the age groups.