Whitfield B. Growdon, MD, discusses the role PARP inhibitors have played in ovarian cancer since their introduction to the field, the updated clinical trial data that contributed to the indication withdrawals for these agents, and where future research in this area may be headed.
Regulatory changes in the ovarian cancer treatment landscape have revealed the importance of reframing the role of PARP inhibitors in this disease, including considering the possibility of their increased potential in the up-front setting, according to Whitfield B. Growdon, MD.
In 2022, the FDA limited the indication for niraparib (Zejula), once approved for patients with homologous recombination deficient (HRD)–positive advanced ovarian, fallopian tube, or primary peritoneal cancer who had received at least 3 prior lines of chemotherapy, to only first-line maintenance therapy in responders to first-line platinum-based chemotherapy and second-line maintenance therapy in those with BRCA-mutant disease.1 This decision was based on final overall survival (OS) findings from the phase 3 NOVA trial (NCT01847274), in which the OS hazard ratio (HR) was 1.06 (95% CI, 0.81-1.37) in the cohort of patients without germline BRCA mutations who received the agent as second-line maintenance.2 That same year, the FDA also removed the indication for olaparib (Lynparza) in patients with germline BRCA-mutated ovarian cancer who have received at least 3 prior lines of chemotherapy, based on findings from an OS subgroup analysis of the phase 3 SOLO3 trial (NCT02282020), in which the OS HR was 1.33 (95% CI, 0.84-2.18) in the population that had received at least 3 prior lines of chemotherapy.3
“Most providers in my field are well aware that this is one of the most important changes that’s occurred in the care of patients with ovarian cancer,” Growdon said in an interview with OncLive®.
In the interview, Growdon discussed the role PARP inhibitors have played in ovarian cancer since their introduction to the field, the updated clinical trial data that contributed to the indication withdrawals for these agents, and where future research in this area may be headed.
Growdon is a member of the faculty in the Department of Obstetrics and Gynecology and the director of the Gynecologic Oncology Fellowship Program at the NYU Grossman School of Medicine in New York, New York.
Growdon: We saw a flurry of FDA approvals over the past 8 years or so, basically characterizing the use of PARP inhibitors. Three specific [agents] have been FDA approved: rucaparib [Rubraca], niraparib, and olaparib. They were used for treatment, for second-line maintenance after a platinum-sensitive recurrence, and as first-line maintenance. Initially, we used them for treatment, then we used them for second-line maintenance, then we had more trials [that supported moving them] into up-front maintenance.
Over the past 12 months, many FDA approvals have been rescinded as a result of more mature data coming out from these initially wildly positive trials. Some exploratory analyses looking at OS suggested a signal in some of these trials that there was actually harm associated with the utilization of PARP inhibitors. In our community, where we’re proponents of new therapies and were excited about PARP inhibitors, all of us were crestfallen that many of the FDA approvals were taken away.
[Regarding] the loss of these FDA approvals, are these a warning signal? [Will these withdrawals also] happen in the places where we think PARP inhibitors are important and safe right now? In 2016, we thought certain activities were safe. Now, 7 years later, we’ve come full circle, and some of the FDA approvals have been rescinded.
In the past 12 months, the FDA, in concert with the companies that make these medicines, got more updated OS data. These OS data suggested trends toward decreased OS for patients who had been randomized to get PARP inhibitors. Specifically, this was in the treatment phase of care for ovarian cancer, as well as the second-line maintenance phase of ovarian cancer.
That was a bit surprising because initially, these trials had been designed to be registrational FDA approval trials, and they were designed with a primary end point of progression-free survival [PFS]. Upon their first publication, they met that primary end point, and they had excellent response rates. The trials in the treatment phase, for instance, were looking at response rates and PFS.
The SOLO3 trial is a great example. [This trial] applied olaparib to patients with [recurrent] ovarian cancer who had measurable disease and a known germline BRCA gene mutation. Olaparib is a great medicine in that setting. It’s been shown to be effective in phase 2 trials. [SOLO3] found that the PFS was statistically significant in favor of olaparib, and better response rates [were seen].
When [the investigators] looked at OS, which was not part of the initial publication and was recent data that came out in [August 2022], they found that in patients who had received 3 or more prior lines of chemotherapy, that OS decreased by 10 months. When they looked at the cohort that had only received 2 prior lines of therapy, they still saw a bit of an OS benefit. However, the FDA and the company decided to remove the whole [later-line] label because of that.
Many of us in the community were a bit surprised by 2 things. One was that the OS signal was a secondary end point that was not necessarily a powered end point for the trial. [Two], these were not statistically significant changes in OS. They were just HRs that were trending in the wrong direction. I think the FDA got nervous about this.
A similar [withdrawal] happened with the use of niraparib as a second-line maintenance therapy after platinum-sensitive recurrence. The NOVA trial came out in 2016 and was a blockbuster. Its’ Kaplan Myers curves were exceptionally good and showed benefit across all strata analyzed, meaning patients with BRCA gene mutations, patients with HRD-positive disease, and patients with HRP-positive disease. [The investigators] saw statistically significant PFS benefits [in those populations].
[However], when they looked at their OS signal, not unlike SOLO3, in this more heterogeneous population, they found that patients who were HRD positive had an HR for OS that was worse and suggested a survival decrement. In the patients with germline BRCA mutations, they still saw a positive OS signal. But the HRs were worse in the non–BRCA-mutated population.
Again, these [results] were not statistically significant. They were secondary outcomes. However, because OS is such an important end point, the FDA pulled the approval of niraparib in patients without a BRCA gene mutation for second-line maintenance. [Regarding] second-line maintenance and treatment with PARP inhibitors, only a small and narrow window of patients qualify for that medicine.
All these trials required patients to be PARP naïve. With the blockbuster trials that have come up since those trials [that investigated these agents as] up-front maintenance, it’s uncommon to have a patient with recurrent ovarian cancer and either high-grade serous or high-grade endometrial cancer who has not seen a PARP inhibitor already. While these changing FDA approvals sound like we’re losing ground and patients are losing treatments, it may be that they’re not losing that much. Many of them have already gotten PARP inhibitors, and in theory, wouldn’t be eligible for [later-line PARP inhibitors], or would be eligible but wouldn’t have the same responses or benefits that we would expect, because they weren’t PARP naïve. They don’t fit the exact eligibility criteria of those trials, so it’s hard to say that the [trial] outcomes would be generalizable to their outcomes.
I was surprised by the treatment indications [the FDA removed for niraparib]. Unlike olaparib, which had a treatment indication for germline BRCA-mutant disease, niraparib had an indication for fourth-line therapy for patients with tumors that were either BRCA or HRD positive, which was also pulled. The reason why was that [regulatory] trial, [the phase 2 QUADRA trial (NCT02354586)], was a single-arm phase 2 trial, so niraparib got an FDA approval for fourth-line therapy in ovarian cancer partially because there was no other medicine in that space at the time. However, [this trial] had no comparator arm, so the FDA, shortly after the [NOVA] data came through, [decided that] because it did not have a comparator arm, and worrisome data [had been published] from [NOVA showing] that OS might be decreased after 3 or more lines, [they would pull] that approval, thinking we don’t have enough data.
Does this mean it’s pulled forever? I don’t think the FDA works that way. If new data were to come to light, they might reconsider. However, for the time being, that is no longer a treatment option for us. Many of us have eyes toward trying to get PARP inhibitors in the up-front setting for most of our patients, because it seems like there are shifting fault lines in the recurrent setting.
[Are the FDA withdrawals of some PARP inhibitor indications] a tragic change? I would argue, I don’t think so. I think they are a signal. [The OS benefits with olaparib and niraparib in the later-line setting were] not statistically significant, [but OS] wasn’t the primary end point [in the trials that informed the withdrawals]. I take [this news] with a grain of salt.