PARP Inhibitors Pave the Way to Cure in Ovarian Cancer

Erin K. Crane, MD, MPH

Following the results of the SOLO-1 trial, maintenance PARP inhibitors have become the standard of care for patients with BRCA-mutated ovarian cancer but overall survival (OS) data are needed to confirm their potentially curative benefit, according to Erin K. Crane, MD, MPH, who added that in the chase to achieve cure, several PARP combinations are under exploration.

Initial data from the SOLO-1 trial indicated that patients with advanced BRCA-mutated ovarian cancer who received maintenance olaparib (Lynparza) following platinum-based chemotherapy experienced a 70% reduction in the risk of progression or death versus those who received placebo.¹ Five-year follow-up data revealed a median PFS of 56 months in the olaparib maintenance arm versus 13.8 months in the placebo arm; the PFS rates at this time point were 48.3% and 20.5% respectively.²

“From the SOLO-1 trial, we concluded that PARP maintenance in patients with somatic or genomic BRCA mutations is, without a doubt, standard of care,” said Crane. “We still don't have the overall survival [OS] data, so I hesitate to use the word ‘cure,’ but we are curing some of those patients, which is really exciting.”

To further build on the success seen with PARP inhibitors, ongoing trials are examining these agents in several novel combination with either chemotherapy, immunotherapy, and targeted therapies like HDAC inhibitors, TKI inhibitors, and monoclonal antibodies, added Crane.

In an interview with OncLive® during the Institutional Perspectives in Cancer webinar on Ovarian Cancer, Crane, a gynecologic oncologist at Levine Cancer Institute, of Atrium Health, discussed pivotal trials examining the role of PARP inhibitors in the maintenance setting and emerging approaches to bring the field one closer to curing more patients with ovarian cancer.

OncLive®: What is the role of maintenance PARP inhibitors in ovarian cancer?

Crane: The role of maintenance therapy for patients with ovarian cancer is really 2-fold. First, we want to hopefully decrease the risk of recurrence. We still don't have finalized OS data from the trials, but we're really hopeful that maintenance may help prevent [the disease] from coming back. We also want to extend the amount of time before [the disease] comes back if it does come back. We know, especially from some of the quality-of-life data that we've seen, that these patients tend to do pretty well and can have a really good quality of life [QoL] after their initial treatment. Hopefully, [this will] extend the duration of this before [patients] have to go on subsequent treatments.

Could you expand on the impact of the SOLO-1 trial on maintenance treatment?

Patients who were enrolled on SOLO-1 had either genomic or somatic BRCA mutations and they had completed first-line therapy with a platinum-based [agent]; they had either a complete or partial response to treatment.

Participants were randomized in a 2:1 fashion to receive olaparib [Lynparza] maintenance versus placebo. We found that patients who were randomized to olaparib experienced a much greater improvement in PFS and a decreased risk of recurrence compared with those who received placebo.

The most recent data that were presented during 2020 ESMO Virtual Congress, showed that the patients who received olaparib had a 56-month PFS, whereas those on placebo really only had [a PFS of] 14 months; this is a huge difference for those patients. We're really hopeful that this [approach] is going to impact OS, but we don't have those data yet.

The PAOLA-1 trial included a similar population to that of SOLO-1. What was learned from this research?

These were patients who had completed first-line treatment, but in this group, patients regardless of their BRCA mutational status were randomized to bevacizumab [Avastin] with initial treatment. That was different from the other groups. They received either received bevacizumab alone or bevacizumab in combination with olaparib. Patients who were in the combination group with bevacizumab and olaparib had a longer PFS; all-comers [had a median PFS of] 22 months in the combination versus 10 months. One of the things that's a bit harder for gynecologic oncologists to figure out is how to use these data.

For those of us who are already using bevacizumab in the up-front setting and the maintenance setting after frontline treatment, it's a no-brainer to add olaparib. For those of us who don't necessarily use it all the time or use more of a risk-based stratification to use it in patients, the data can be a little bit harder to interpret because there was not an olaparib-only arm.

How are the results of the PRIMA trial being interpreted in clinical practice?

This is a really exciting study, as well, because it included all comers. In a similar setting, patients who had a response to platinum-based chemotherapy in the frontline setting after completion of treatment were randomized in a 2:1 fashion to niraparib [Zejula] versus placebo. For all comers, we saw about a 22-month versus a 10-month benefit in median PFS. The patients who had homologous recombination deficiency (HRD), however, really had the most benefit. The patients who did not have HRD really only garnered barely a 3-month benefit. I think this has been practice-changing in that we discuss [this approach] with all of our patients and [it has also impacted] how we test patients when they're initially diagnosed.

How were you approaching testing before these results?

Previously, many of us had been sending patients for germline testing. The somatic testing happened later in the course of treatment when we were looking for other treatment options. Now, many of us are proceeding with somatic testing in the frontline setting to obtain the HRD score and triage patients; [we used this to decide] whether they should receive niraparib maintenance, or PARP maintenance for that matter, after frontline therapy.

It is important to know, however, that niraparib was FDA-approved for [use as] frontline maintenance, regardless of HRD status or BRCA mutation status. You certainly could make an argument to use it in all patients. However, as providers, 1 of the things we struggle with is that even though PARP inhibitors are generally well tolerated, they do have adverse effects.

For a patient who just completed a pretty rough course of chemotherapy, to offer them a PFS of only 2-3 months in this setting with a drug that has some toxicity is a discussion between the patient and the provider. Those data are a little more controversial [in terms of knowing] how to use this [appropriately] in that population.

Are there any ongoing trials being done in the maintenance setting that you would like to highlight?

We're always thinking about what we can do better for patients. What can we combine with these drugs to make them work better, to improve PFS or even OS, [to achieve] a cure? Some trials are looking at combining PARP inhibitors with immunotherapy; those results are certainly exciting and are something to look forward to. Other trials are looking at PARP inhibitors combined with chemotherapy in the frontline setting. That [approach] can be a little more toxic on the bone marrow; it’s a little bit harder to get patients through. Then there is a whole array of [efforts that are] combining PARP inhibitors with other targeted molecular therapies, such as HDAC inhibitors, TKI inhibitors, and monoclonal antibodies in hopes that there will be a synergistic effect in combining these maintenance therapies.

What challenges remain in this setting?

As physicians, we still struggle with the fact that we're always talking about PFS, and it's generally agreed upon that this should be our end point. However, when we really start talking with patients and being honest with them, [we know that] it's still very hard for us to cure them of their disease. Hopefully, PARP inhibitors are helping to pave the way for us to do that. Combining PARP inhibitors with other drugs in the maintenance setting to help improve PFS or even OS in these patients is something that is still a challenge.

Of course, there is always the challenge of managing patients with recurrent disease, especially patients who are HRD negative. We know that not only do they not respond as well to PARP inhibitors, but it's harder to get them optimally debulked at the time of surgery. They also tend to not respond as well to platinum-based therapy. This is a particular patient subgroup that really needs help in terms of extending their lives and their PFS.

References

1. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505. doi:10.1056/NEJMoa1810858
2. Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year follow-up (f/u) from SOLO1. Ann Oncol. 2020;31(supp 4):S613. doi:10.1016/j.annonc.2020.08.950