PARP Inhibitors Redefine the Rapidly Changing Ovarian Cancer Landscape

Updated research showing benefits with olaparib (Lynparza) and niraparib (Zejula) in patients with ovarian cancer, regardless of BRCA mutation or homologous recombination deficiency (HRD) status, is setting the stage for continued advances with these agents that may fulfill several unmet needs in this population, according to Erin K. Crane, MD, MPH.

“PARP inhibitors have exploded over the past 5 to 10 years,” Crane said in an interview with OncLive®. “It’s important to keep up to date with these changes and to have discussions like this so everyone is on the same page about what the indications are and what indications are withdrawn.”

In the interview, Crane described practice-changing findings from upfront trials with niraparib and olaparib, contextualized the significance of the manufacturer restrictions of later-line PARP inhibitors for ovarian cancer, and predicted further research efforts that may be on the horizon in this population.

The phase 3 SOLO1 trial (NCT01844986) randomized patients with newly diagnosed, BRCA-mutated ovarian cancer to up to 2 years of either maintenance olaparib or placebo.¹ At 7 years of follow-up, the median overall survival (OS) was not reached in the olaparib arm vs 75.2 months in the placebo arm. With a median follow-up of 3.5 years, long-term progression-free survival (PFS) data from the phase 3 PRIMA trial (NCT02655016) showed that the median PFS was 24.5 months in patients with HRD-positive disease who received niraparib vs 11.2 months in those who received placebo.² Additionally, in the overall phase 3 PAOLA-1 trial (NCT02477644) population, treatment with olaparib plus bevacizumab (Avastin) led to a 5-year OS rate of 47.3% vs 41.5% in those who received placebo plus bevacizumab.³ Crane emphasized how the findings from each of these studies have reinforced the frontline PARP inhibitor armamentarium in ovarian cancer.

Crane is an associate professor in the Division of Gynecologic Oncology at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

OncLive^®: What clinical trials have solidified the upfront use of PARP inhibitors across subsets of patients with ovarian cancer?

Crane: [Regarding] PARP inhibitor maintenance in the upfront setting, [key trials include] the SOLO1 trial, the PRIMA trial, and the PAOLA-1 trial. SOLO1 [enrolled] patients with BRCA mutations, either somatic or germline, who were randomized to olaparib vs placebo after completion of chemotherapy. That [trial] has continued to show drastic benefit for patients with BRCA mutations who were randomized to olaparib. At 7 years, 67.0% of patients [who received olaparib] were still alive vs 46.5% in the placebo group. The benefit has been sustainable. That’s been practice changing and has changed the lives of our patients.

The PRIMA trial [evaluated] niraparib in the maintenance setting, but instead of just [enrolling] patients with BRCA mutations, it included all-comers, [including] those with BRCA mutations, those with HRD-positive disease without BRCA mutations, and those with homologous recombination–proficient [HRP] tumors. In all groups, [niraparib] demonstrated some benefit. In [the primary analysis in] all-comers, [niraparib and placebo produced a median PFS of] 13.8 months vs 8.2 months, [respectively]. In the HRD-positive population, including those with BRCA mutations, [the median PFS was] 21.9 months vs 10.4 months [with placebo], a big benefit. That allowed niraparib to get an FDA indication for all [adult] patients [with ovarian cancer who responded to first-line platinum-based chemotherapy], agnostic of whether they had BRCA mutations or HRD-positive disease in the maintenance setting.

Finally, the PAOLA-1 trial randomized patients to olaparib plus bevacizumab vs bevacizumab alone in the maintenance setting after the completion of chemotherapy, regardless of HRD or BRCA status. There was a [median PFS] benefit of 22.1 months vs 16.6 months in the patients who received olaparib plus bevacizumab vs bevacizumab alone, [respectively]. [The olaparib combination led to a] much higher magnitude benefit in patients with HRD-positive disease, including those with BRCA mutations, [producing a median PFS of] 37.2 months vs 17.7 months [with bevacizumab alone], which led to FDA approval [of maintenance olaparib plus bevacizumab] for patients with HRD-positive disease [defined by a deleterious or suspected deleterious BRCA mutation, and/or genomic instability].

[We have seen] great benefit across the board for patients with niraparib, olaparib, and the bevacizumab indication. Importantly, each of these study populations differed a bit, so the indications differ a bit as well.

In 2022, following evidence of safety concerns, the manufacturers of niraparib, olaparib, and rucaparib (Rubraca) withdrew indications for these agents in patients with heavily pretreated, BRCA-mutated ovarian cancer. What do these changes mean for patients with ovarian cancer, and how have these withdrawals influenced your practice?

There have been many updates and changes. The phase 3 NOVA trial [NCT01847274], in which patients with platinum-sensitive, recurrent ovarian cancer were randomized to niraparib vs placebo, showed an improvement in PFS [with niraparib], but longer-term data showed a detriment to OS. [The niraparib] indication has changed only for patients with BRCA mutations. The indications for olaparib haven’t changed, but there may be some [changes] coming down the pike. We’re all waiting to see what happens. [Additionally, the manufacturer of] rucaparib withdrew [the indication for this agent in third- or later-line BRCA-mutated ovarian cancer].

The question is: [Do these withdrawals] matter that much? For patients who develop treatment-related acute myeloid leukemia or myelodysplastic syndrome, yes, it’s devastating. However, the reason we’re asking that question is, [although] these studies are not obsolete, we’ve moved PARP inhibitors to the frontline maintenance setting. Any [patients with] BRCA-positive, HRD-positive, and to some extent, HRP disease, are going on PARP inhibitors. If they’ve already received PARP inhibitor treatment, are we going to put them back on PARP inhibitors in the recurrent platinum-sensitive setting? Probably not. Progression on PARP inhibitors is probably a good indication of overall platinum sensitivity. We probably won’t rechallenge those patients with PARP inhibitors.

This is a bigger question, though, and a topic of debate for patients with BRCA-positive disease [who have] had a long disease-free interval where they finish their PARP inhibitor maintenance for 2 or 3 years and then have a recurrence later. Do we rechallenge those patients? That’s a bigger question for all of us, and hopefully, we’ll have more data on that.

What future developments with PARP inhibitors in ovarian cancer are you looking forward to?

The PALOA-1 study is a good example of how to combine a PARP inhibitor with another targeted therapy. Tons of studies are combining PARP inhibitors with other targeted therapies. Those results will be exciting and may even further extend PFS and OS for eligible patients.

[We should also investigate] mechanisms of PARP resistance and why patients eventually become resistant to PARP inhibitors to see if there’s any way to reverse that resistance. This is challenging, but definitely a worthwhile issue to pursue for those patients.

The HRD-positive population and patients with BRCA mutations do much better [with PARP inhibitors than other patients with ovarian cancer]. However, the patients with HRP disease need other therapeutic options, because they’re not good candidates for PARP inhibitors. With all this excitement about the benefits of PARP inhibitors, we don’t want to forget that population that we know will probably do worse.

What is your main message for colleagues regarding the role of PARP inhibitors in ovarian cancer?

At this point, any patient with an HRD-positive tumor or a BRCA mutation should be placed on a PARP inhibitor for maintenance therapy. [When asking] whether patients in the recurrent, platinum-sensitive setting should still be placed on PARP maintenance, the answer is probably not for patients with BRCA mutations or those in extenuating circumstances.

What ongoing ovarian cancer research is Levine Cancer Institute participating in?

Levine Cancer Institute has been great at opening phase 1 trials. We have a couple of phase 1 trials open now investigating different therapeutics in the platinum-resistant setting, which is important for our patients. We’re trying to get a project up and running investigating circulating tumor DNA, which has exploded and is on the horizon, but which none of us know how to put into practice. We’re active members of NRG and GOG, so we have many trials up and running. We’re excited to be participating and bringing those new treatments to the forefront for our patients.

References

1. DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1-GOG 3004 trial. J Clin Oncol. 2023;41(3):609-617. doi:10.1200/JCO.22.01549.
2. Gonzalez Martin AJ, Pothuri B, Vergote IB, et al. PRIMA/ENGOT-OV26/GOG-3012 study: updated long-term PFS and safety. Ann Oncol. 2022;33(7):S789. doi:10.1016/j.annonc.2022.07.658
3. Ray-Coquard IL, Leary A, Pignata S, et al. Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients with newly diagnosed advanced ovarian cancer (AOC). Ann Oncol. 2022;33(7):S1396-S1397. doi:10.1016/j.annonc.2022.08.025