Promising data with PARP inhibitors, specifically olaparib and niraparib, are showcasing this class of agents’ activity in early and later-line settings of ovarian cancer, explained Kathleen Moore, MD.
Kathleen Moore, MD
Promising data with PARP inhibitors, specifically olaparib (Lynparza) and niraparib (Zejula), are showcasing this class of agents’ activity in early and later-line settings of ovarian cancer, explained Kathleen Moore, MD.
For example, the phase III SOLO-1 trial evaluated olaparib as frontline maintenance therapy for women with BRCA-positive advanced ovarian cancer. Results, which were presented at the 2018 ESMO Congress, showed that the median progression-free survival (PFS) by independent central review was not reached in the olaparib arm (n = 260) versus 14.1 months in the placebo arm (n = 131) at a follow-up of 41 months.1Additionally, the investigator-assessed PFS in the olaparib arm was not reached compared with 13.8 months in the placebo arm (HR, 0.30; 95% CI, 0.23-0.41;P<.0001).
Findings from the phase II QUADRA study showed that niraparib exhibited an overall response rate of approximately 30% in this subset of patients when used in the fourth- or later-line setting.2Longer median PFS was observed in patients who were sensitive to their last line of platinum.
In an interview withTargeted OncologyTMat the meeting, Moore, director of the Oklahoma TSET Phase I Program and an associate professor of gynecologic oncology at the Stephenson Cancer Center, University of Oklahoma, reflected on these data as well as the future for PARP inhibitors in this malignancy.
Targeted OncologyTM: Could you share some insight on the importance of the SOLO-1 data presented at the 2018 ESMO Congress?
Moore: I had the privilege of presenting SOLO-1, but it was an international team effort. SOLO-1 addresses one of the biggest problems in advanced ovarian cancer. We have a highly treatable disease, but not many women live disease-free long-term. Cure rates are lowdismal in fact, at about 10% to 15%. Really, the only way we are going to change that is improve frontline therapies. There has been a lot of effort to do that over the years in clinical trials, mostly of all-comer populations, with no impact on overall survival but some incremental improvement in PFS. Since the discovery of platinum, we have not markedly improved disease-free survival. SOLO-1 sought to show that we can do that.
It is a randomized phase III trial of patients with advanced-stage ovarian cancer who also harborBRCAmutations. They received standard of care chemotherapy and they had to be in either complete or partial response to that treatment. They have to have had an attempt at cytoreductive surgery and be in excellent performance status. If they met all those criteria and enrolled, they were randomized to receive olaparib tablets 300 mg twice daily or placebo. That treatment was continued until disease progression, or if patients were disease-free at 2 years they were stoppedunless they came onto study with a partial response and still had evidence of disease at that 2-year mark, but it was stable.
The primary endpoint was PFS as assessed by the investigator, and it was measured from the time of randomization. There are a number of secondary endpoints that are very important, one of which is PFS as assessed by blinded central review. Another is PFS2, which is the time from randomization until the second recurrence among those patients who recur. That is a very important endpoint, especially in the European Union where it is a regulatory endpoint, because it is felt to recapitulate what you would see in overall survival. There were also quality-of-life endpoints.
Patients who were enrolled on SOLO-1 were of excellent prognostic factors. Again, this is a population that is unlike any that is being recruited into current frontline studies. Over 60% of them had a frontline surgery, and of those, 75% were debulked to no gross residual [disease]. Eighty percent of them entered the study with complete clinical responses. These responders were then randomized.
In the group of women who received placebo, the median PFS was 13.6 months measured from the end of chemotherapy. In the group of women who were randomized to olaparib, we have not reached the median PFS yet. They are doing remarkably well. The difference in the survival curves gives us a hazard ratio of 0.3, which really translates to a 70% reduction in the risk of recurrence with olaparib. Even though we have not met the median for the olaparib group, there were a number of sensitivity analyses done that account for the potential of bias, to be sure that we are confident in the hazard ratio estimate as assessed by the investigators; all of those were very consistent. Two of them did give us the estimated median PFS for that group of 46 to 49 months. PFS was also still statistically significant among patients who did recur.
These are unprecedented results in frontline ovarian cancer that we hope that it translates to more women remaining disease-free long-term. Are we curing more patients? We can't say that yet, we are going to have to follow these patients for years. We are going to do that; we are going to keep a close eye on them for as long as it takes. It should result in a rapid change in the standard of care.
Moving onto niraparib, could you reflect on what was seen with the QUADRA study?
The PARP inhibitors are more similar than they are different, but one of the key differences of niraparib is that it is a once daily dose, which is nice. Niraparib was actually the first PARP inhibitor to gain FDA approval in the maintenance setting for recurrent disease. We do have a lot of experience with niraparib in platinum-sensitive patients. We have almost definitively shown, with niraparib, olaparib, and rucaparib (Rubraca), that there is benefit across all subgroups. This is why you have approvals regardless of biomarkers in the platinum-sensitive recurrent maintenance setting.
One of the questions that we still have, that we won't know the answer to pending results is, “Do you need that induction chemotherapy and then maintenance? Or can you just use a PARP inhibitor as treatment? Is that equivalent in a platinum-sensitive setting? And then, how efficacious is a PARP inhibitor in a platinum-resistant patient with aBRCAmutation, homologous recombination deficiency (HRD), or neither?”
In the QUADRA study, they sought to evaluate the use of a single-agent PARP inhibitor in a difficult-to-treat population. The primary endpoint for QUADRA was looking at patients who are sensitive to their last platinum, positive HRD, as well as looking at efficacy. [Investigators] wanted to look across the board at all subgroups of patients to see what the potential benefit of niraparib could be. There are a lot of patients who do not fall into the current indication for the use of olaparib, which is germlineBRCA-mutant, with at least 3 lines of chemotherapy in the United States, or rucaparib in 2 lines.
QUADRA was the largest single-agent PARP study to date with 463 patients. We had a response rate of 27%, and 4 or 5 lines of therapy. In heavily pretreated, and not necessarilyBRCA-positive patients. In subgroups, we did not see a high response rate, but we did see a lot of disease stabilization out to 6 months. When you are in fourth- or fifth-line setting using an oral therapy for platinum-resistant disease and you have someone go 6 months 25% of the time, that is a clinically meaningful endpoint for patients. It is a hard regulatory endpoint to argue as a means for approval, although I hope we can. QUADRA really gives us a sense of what kind of clinical benefit can be seen beyond shrinking a tumor 30%.
Here at the 2018 ESMO Congress, we just updated the 2018 ASCO Annual Meeting presentation to focus on just theBRCA-positivepatients. There are a lot of patients out there withBRCAmutations who are long-term survivors in the fourth, fifth, or sixth line of therapy. These data really show that efficacy doesn't stop, and those patients will still benefit from the use of a PARP inhibitor, so we should keep that on their list of therapies.
Looking at the 3 PARP inhibitors approved in ovarian cancer, what does the future hold for this class of agents?
There are so many exciting things coming in the next few years, so it is hard to answer that. Right away, we are going to see adoption of frontline olaparib forBRCApatients. That is going to unleash a whole series of questions. First, what percentage of those patients are now cured and never need another therapy? I want to know that. A certain percentage of patients are going to recur. When they recur and are sensitive to platinum, do you reuse a PARP inhibitor? We don't know. We need to know if a PARP inhibitor can work again.
Next year is going to be an exciting year. There are data coming out with PARP inhibitors beyondBRCA. We have the PAOLA-1 study, which is in all-comers. That will be the first study with PARP inhibitors looking at a biomarker-agnostic endpoint first. If that is meaningfully positive, then everyone is going to have PARP and bevacizumab in the frontline setting.
There is also PRIMA, which is a niraparib frontline study being done and is maturing. It is looking at switch-maintenance niraparib, also in an all-comers group of high-grade serous and high-grade endometrial cancers. They are collectingBRCAstatus, but they are looking at HRD as their primary endpoint.
VELIA is a study of velipariba PARP inhibitor that does not have an approval yet. It is the only one that you can combine with full-dose chemotherapy. Likely we will see some preliminary data or maybe the primary endpoint for that next year.
Most of us think that one of those will be positive, which will expand use in the frontline setting. The same questions about recurrence will come up, though. The field is wide open, and we see agents coming into the space targeting DNA damage response and various pathways.
There is also the whole field of immunotherapy. We don't have enough data to comment on yet, except for the single-agent findings, which are disappointing. There was a signal, but not enough of one. That is the story yet to be told. We are years out from seeing results from that. We anticipate the findings from the JAVELIN 100 and JAVELIN 200 studies in 2019. 2019 is going to be an interesting time for gynecologic cancers. We are going to get a little more confused, but we are not confused about PARP in the frontline setting forBRCAthat is a definite.