PARP Inhibitors Represent Effective Upfront Ovarian Cancer Treatment Options

Whitfield B. Growdon, MD

Frontline maintenance therapy with PARP inhibitors may strengthen recurrence prevention strategies in patients with newly diagnosed ovarian cancer, according to Whitfield B. Growdon, MD.

“I have a lot of optimism about [PARP inhibitors in] the upfront setting. [That may] be the standard of care moving forward,” Growdon said.

In an interview with OncLive®, Growdon shared the potential implications of first-line PARP maintenance in newly diagnosed ovarian cancer, the importance of treating patients with effective therapies as early as possible, and where combination regimens could fit into the treatment paradigm going forward.

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.

OncLive: What research is needed to solidify the role of PARP inhibitors in the ovarian cancer armamentarium?

Growdon: The future will be focused more on maintenance therapy in the upfront setting. We will learn more about the overall survival [OS] signals. The question that’s on all our minds is: Are we curing more patients?

When I was a fellow, one of my favorite attendings explained to me that about 10% of patients with advanced-stage ovarian carcinoma, that is, high-grade serous or high-grade endometrioid [disease], become cured. They get an upfront surgery and chemotherapy, and the cancer never comes back. But that means 90% of the time, [the cancer does come] back, and it becomes something to contend with. In general, it shortens patients’ lives. They don’t survive that cancer because it’s not curable. Many of the advances we have made over the past 30 or 40 years have improved patients’ quality of life, allowed them to live sometimes years longer with their cancer, but never changed the stars. All of us hope for something better.

What key data may inform the efficacy of maintenance olaparib in newly diagnosed disease?

The [phase 3] SOLO-1 trial [NCT01844986], which [investigated] olaparib [Lynparza] maintenance for patients with high-grade serous endometrial carcinoma with a BRCA mutation, found that the median progression-free survival [PFS] was 56.0 months in patients who received olaparib and 13.8 months in patients who received placebo. One of our famous trials, the [phase 3] GOG 172 trial [NCT00003322], which was the one of the best intraperitoneal chemotherapy trials, [showed] a median OS of 65.6 months [with intraperitoneal chemotherapy]. Suddenly, we have [SOLO-1], where the median PFS [was close to the median OS in GOG 172]. That is a blockbuster. That difference is 1 year vs 5 years.

The way the Kaplan-Meier curves look in the 7-year [SOLO-1] OS update, the median OS of the olaparib cohort hasn’t been met yet. The median OS will be more than 7 years. That hasn’t reached statistical significance yet; the P value is .0004. [the OS] needs a better P value than that [to reach statistical significance].

We also suspect that in the next update, SOLO-1 will have an OS benefit for patients with BRCA mutations. That suggests that [more than] 10% [of patients] will get better with this therapy. We might cure more patients out of the gates. This has always been the adage, that we do everything possible in the upfront setting to get patients to a cure, because if the cancer comes back, it’s almost impossible to cure it. That’s a hard reality many of us face daily. 

There’s also the [phase 3] PRIMA trial [NCT02655016], which was interesting. This trial [included] patients across all genomic backgrounds, meaning patients with BRCA mutations, patients with homologous recombination­–deficient [HRD] disease, and patients with homologous recombination–proficient disease. What this trial found [with niraparib (Zejula)] was similar [to what SOLO-1 found with olaparib].

We don’t have a mature OS update [from that study yet]; the OS data in the initial publication were immature. However, the PFS was updated in 2022. The initial PFS data that were seen in the publication in 2019 have stayed true to form. We haven’t seen alterations in the signals, meaning we don’t think the same effects that befell niraparib with the [phase 3] NOVA trial [NCT01847274], where we saw OS decrement, [will happen in] the upfront setting. We need to wait and see.

What concerns exist regarding second- and later-line treatment sequencing in patients with ovarian cancer?

Many of us are a bit anxious about the way PARP inhibitors perform in patients without BRCA mutations. Even in HRD-positive populations where there’s more PFS benefit, we are worried that that PFS benefit will be eclipsed by the induction of chemotherapy resistance on the second-line therapeutic end. That was observed in the [phase 3] SOLO2 trial [NCT01874353] and a bit in the NOVA trial, which are second-line maintenance trials.

In the PRIMA trial, HRD-positive patients [achieved a] 22.1-month median PFS [with niraparib] vs a 10.9-month [median PFS with placebo]. If we give patients PARP inhibitors, [we may] see a benefit of 8 months. [However], when those patients develop a recurrence of their cancer, [and we] give them second-line therapy, it may be that in the patients who got [maintenance with a first-line PARP inhibitor, such as] niraparib for 2 to 3 years in NOVA or 2 years of [olaparib] maintenance in SOLO2, that extra therapy makes them more resistant more to their second therapy. Therefore, their OS looks worse because they are resistant to all subsequent therapies, whereas patients who didn’t get [PARP inhibitors] up front may be more sensitive and have a longer runway in the end. That’s the concern and the signal we were seeing.

With SOLO-1, it doesn’t look like that’s true. If you analyze the time to second progression [PFS2] and subtract the initial PFS from the PFS2 to understand the response rates to the second-line therapy, it looks like they still favor the patients who got olaparib. In PRIMA, we don’t quite know yet. We’re waiting on those data. We’ll have to examine that carefully.

The fear is that if patients don’t get cured with [PARP inhibitors] up front, they may be worse off having gotten the maintenance [therapy]. That will be a question all of us will need to grapple with. That’s cast a bit of a pall on the data. We worry about any types of resistance signals we could be inducing with PARP inhibitors. It will be incumbent upon our translational researchers to figure out PARP resistance mechanisms and what medicines should be applied for patients who develop PARP resistance.

These maintenance trials [ran] for 2 to 3 years after [patients received] initial therapy. A significant subset of patients develop recurrence while they’re on their PARP inhibitor. They’re not patients who [received the PARP inhibitor for] 3 years, stopped, and developed a recurrence 2 years later. They’re developing recurrence whilst on PARP inhibitors. PARP inhibitors have actions that can be associated with platinum or chemotherapy resistance, based on [findings from] a SOLO2 ancillary study that investigated what happened after [the trial ended].

The jury’s out about what will happen in the upfront setting. Whenever we see [an agent] that initially works well but then is associated with possibly worse survival on the back end, we worry we have changed the biology of the cancer and turned it into [a disease] that is worse than it would have been if we had never touched it. That’s the concern.

How might combination therapies complement or complicate PARP inhibitor efficacy?

In the beginning, we were interested in merging PARP inhibitors with other types of therapies like immunotherapy and angiogenic therapy. The [phase 3] PAOLA-1 trial [NCT02477644] added olaparib to bevacizumab [Avastin] for patients across genetic backgrounds. This trial found that adding olaparib was effective for PFS in patients with BRCA mutations and HRD. That trial did not have a single olaparib arm, [so we may] never know whether bevacizumab added any [benefit], because all the arms had bevacizumab.

There’s been criticism of PAOLA-1 because in SOLO-1, which included patients with BRCA mutations, there was a median PFS of 56.0 months [with olaparib] vs 13.8 months [with placebo], whereas in PAOLA-1, in the cohort of patients with BRCA mutations, the median PFS was 37.2 months [with olaparib] vs 21.7 months [with placebo]. [The PFS benefit with olaparib] was still highly statistically significant, but only by around 1 year; it wasn’t a 4-year difference.

Many investigators [noted that] PAOLA-1 had a different population [than SOLO-1 and that we] can’t compare across trials. [PAOLA-1 had] a slightly higher number of patients with stage IV disease and a higher number of patients who had gotten neoadjuvant chemotherapy. [However, that population may not have been] different enough to account for [the lack of those] 3 years of PFS [benefit].

The concerning question that wasn’t written in the New England Journal of Medicine [paper] was: Could bevacizumab be blunting the effect of niraparib? We assume more is more and that [agents are synergistic]. However, [drugs] can conspire against each other. We don’t have preclinical data to suggest that’s true [in this case], but the clinical signal suggests [the PFS is] not as good with bevacizumab and that if you have a patient with a germline BRCA mutation, you might just want to give them olaparib. Many of my colleagues will just give olaparib for patients with lower-risk ovarian cancer.

How do we interpret PAOLA-1? Many of us [decide that] if we have a patient with high-risk ovarian cancer, we can add olaparib if we’ve added bevacizumab, because bevacizumab was associated with an OS benefit in a subset analysis of the [phase 3] ICON7 trial [NCT00483782]. PAOLA-1 says this is safe and effective.

What might the future of PARP inhibitors in ovarian cancer look like?

Emerging research is investigating immune therapy and merging that with PARP inhibition. These trials haven’t been published yet, but there have been some exciting signals. There may be a day when we give subsets of patients immune therapy and PARP inhibition, along with cytotoxic chemotherapy.

There’s even a movement to replace cytotoxic chemotherapy entirely. All of us, for the past 30 years, have given platinum-based therapy with or without paclitaxel. Carboplatin and paclitaxel took the forefront in 2003. That was 20 years ago, and we’re still doing that. There are not many [treatments] in oncology [that we used] 20 years ago [and still do]. Most of us aren’t driving cars from 20 years ago, and yet we treat patients with ovarian cancer the same way [as we did then].

Trials are in the works that are enrolling patients with BRCA mutations and giving them olaparib first, without chemotherapy. Wouldn’t that be amazing if we could eliminate carboplatin plus paclitaxel? All the ports, neuropathy, hair loss, all the things we associate with chemotherapy, could go away. Not that olaparib is a picnic to take; it’s not easy. In SOLO-1, 28.8% of patients needed to dose reduce, and [regarding discontinuation], 11.9% of patients couldn’t get through their maintenance. But that’s maintenance, that wasn’t treatment. Maintenance can be 2 years. I can understand if a patient might not want to do [maintenance] for 2 years. Treatment is a shorter period. Carboplatin and paclitaxel is usually [given for] 15 weeks, [administered for] 6 cycles every 3 weeks.

[Going forward, we may] keep PARP inhibition up front, but merge it with other therapies in particular subsets and tease out which types of tumors respond with these agents. I hope we can begin to look at each tumor like a snowflake, break them down and say, [this tumor has certain qualities], and this cocktail works best in that setting, and we have good prospective data to inform that. This is in the works, and we’re all excited about it. I hope we will push that bar.

I don’t know what I will tell my fellows about the chances of curing patients, but our patients want [cures]. They don’t want to hear that they’re going to live a long time but ultimately, the cancer will overtake our ability to control it. They want to know their curative options. That’s what I want. That’s what I would want for my sister or my mother. I want to get a cure and figure this out. PARP inhibitors are 1 of the biggest steps toward doing that. We are fired up about this and in a healthy way, wary of certain signals.